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Distinct extended amygdala circuits for divergent motivational states
Open accessAbstract
The co-morbidity of anxiety and dysfunctional reward processing in illnesses such as addiction and depression suggests that common neural circuitry contributes to these disparate neuropsychiatric symptoms. The extended amygdala, including the bed nucleus of the stria terminalis (BNST), modulates fear and anxiety, but also projects to the ventral tegmental area (VTA), a region implicated in reward and aversion, thus providing a candidate neural substrate for integrating diverse emotional states. However, the precise functional connectivity between distinct BNST projection neurons and their postsynaptic targets in the VTA, as well as the role of this circuit in controlling motivational states, have not been described. Here we record and manipulate the activity of genetically and neurochemically identified VTA-projecting BNST neurons in freely behaving mice. Collectively, aversive stimuli exposure produced heterogeneous firing patterns in VTA-projecting BNST neurons. By contrast, in vivo optically identified glutamatergic projection neurons displayed a net enhancement of activity to aversive stimuli, whereas the firing rate of identified GABAergic (γ-aminobutyric acid-containing) projection neurons was suppressed. Channelrhodopsin-2-assisted circuit mapping revealed that both BNST glutamatergic and GABAergic projections preferentially innervate postsynaptic non-dopaminergic VTA neurons, thus providing a mechanistic framework for in vivo circuit perturbations. In vivo photostimulation of BNST glutamatergic projections resulted in aversive and anxiogenic behavioural phenotypes. Conversely, activation of BNST GABAergic projections produced rewarding and anxiolytic phenotypes, which were also recapitulated by direct inhibition of VTA GABAergic neurons. These data demonstrate that functionally opposing BNST to VTA circuits regulate rewarding and aversive motivational states, and may serve as a crucial circuit node for bidirectionally normalizing maladaptive behaviours.
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Written from the paper’s full text.
TL;DR
In mice, VTA-projecting BNST neurons comprise opposing glutamatergic and GABAergic subcircuits: aversive stimuli increase glutamatergic activity and suppress GABAergic activity, and optogenetic activation of these pathways produces aversive/anxiogenic versus rewarding/anxiolytic states, respectively. These findings identify a bidirectional BNST→VTA circuit node for motivational and emotional processing.
Key findings
- In vivo antidromic identification found 53/137 BNSTv→VTA projection neurons; aversive stimuli produced heterogeneous firing patterns across these neurons. Identified Vglut2BNSTv→VTA neurons (34/145) showed net enhanced firing during aversive events and shock-associated cues, whereas VgatBNSTv→VTA neurons (33/77) were principally suppressed.
- Circuit mapping showed that Vglut2BNSTv→VTA and VgatBNSTv→VTA terminals formed functional synapses primarily onto non-dopaminergic and medially located dopaminergic VTA neurons.
- Photostimulation of Vglut2BNSTv→VTA produced avoidance of a stimulation-paired chamber, reduced active reward seeking, and anxiety-like open-field behavior; the aversive phenotype was abolished by intra-VTA ionotropic glutamate receptor antagonists.
- Photostimulation of VgatBNSTv→VTA produced place preference, supported optical self-stimulation, and increased open-arm time in the elevated plus maze; these effects were prevented by an intra-VTA GABAA antagonist and recapitulated by direct inhibition of VTA GABAergic neurons. Concurrent VgatBNSTv→VTA stimulation during foot shock reduced freezing and increased later open-arm time/entries.
Methods
- Adult male C57BL/6J, Vgat-ires-cre, and Vglut2-ires-cre mice received stereotactic viral injections (ChR2-eYFP, NpHR) and optical fibers/MEA implants; experiments included anesthetized and behaving in vivo electrophysiology, patch-clamp recordings in VTA slices, unpredictable foot-shock sessions, and optogenetic behavioral assays.
- In vivo electrophysiology used a 16-channel MEA in BNSTv and optical fibers above VTA for antidromic identification; units were classified using spike latency, waveform correlation, and z-score firing changes during foot-shock sessions.
- Behavioral assays included real-time place preference, open field, sucrose self-administration, optical self-stimulation/self-inhibition, elevated plus maze, and foot-shock-induced freezing, with intra-VTA antagonist microinfusions in some experiments.
Limitations
- The paper states that shock artifacts prevented reliable quantification of neuronal firing 500–1000 ms after foot-shock onset, excluding approximately 0.8–1.66% of collected data during the foot-shock session.
- Evident from the text: all experiments used adult male mice, so sex differences and generalization to females are not addressed.
- Evident from the text: the paper does not include a dedicated limitations section; circuit specificity relies on viral targeting, optogenetic manipulation, slice physiology, and pharmacological blockade rather than fully selective circuit-silencing approaches.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“in vivo optically-identified glutamatergic projection neurons displayed a net enhancement of activity to aversive stimuli”
- Also stated in: § Abstract · plain
“Collectively, exposure to the aversive event or associated cues alone enhanced the firing of Vglut2BNSTv→VTA neurons”
§ Distinct extended amygdala circuits for divergent motivational states > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Abstract · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Collectively, aversive stimuli exposure produced heterogeneous firing patterns in VTA-projecting BNST neurons.”
- Also stated in: § Abstract · boosted
“Identified BNSTv→VTA neurons segregated into three functionally distinct classes based on changes in their normalized firing rates throughout the foot-shock session (Supplementary Fig. 3), demonstrating that BNSTv→VTA neurons differentially encode information related to aversive stimuli and their associated contextual cues.”
§ Distinct extended amygdala circuits for divergent motivational states > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Abstract · boosted
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“whereas the firing rate of identified GABAergic projection neurons was suppressed”
- Also stated in: § Abstract · plain
“while simultaneously suppressing the activity of VgatBNSTv→VTA neurons.”
§ Distinct extended amygdala circuits for divergent motivational states > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Abstract · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“activation of BNST GABAergic projections produced rewarding and anxiolytic phenotypes”
- Also stated in: § Abstract · hedged
“Photostimulation of the VgatBNSTv→VTA pathway and direct inhibition of VgatVTA neurons significantly increased time spent in the open arms of an elevated plus maze, indicative of anxiolysis”
§ Distinct extended amygdala circuits for divergent motivational states > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Abstract · hedged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“VgatBNSTv→VTA::ChR2 mice spent significantly less time frozen (Fig. 5h)”
§ Distinct extended amygdala circuits for divergent motivational states > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“as well as significantly more open-arm time and entries in the elevated-plus maze relative to controls (Supplementary Fig. 18)”
§ Distinct extended amygdala circuits for divergent motivational states > Abstract
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In vivo photostimulation of BNST glutamatergic projections resulted in aversive and anxiogenic behavioral phenotypes.”
- Also stated in: § Abstract · hedged
“inescapable activation of this pathway for 20 min in an open field resulted in significantly less center- and more corner-time in Vglut2BNSTv→VTA::ChR2 mice in the 10 min following stimulation offset compared to controls”
§ Distinct extended amygdala circuits for divergent motivational states > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Abstract · hedged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“VTA infusions of a GABAA receptor antagonist prevented the VgatBNSTv→VTA mediated place preference compared to saline injections”
§ Distinct extended amygdala circuits for divergent motivational states > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Vglut2BNSTv→VTA and VgatBNSTv→VTA terminals formed functional synapses primarily onto non-dopaminergic and medially located dopaminergic neurons”
§ Distinct extended amygdala circuits for divergent motivational states > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“activation of BNST GABAergic projections produced rewarding and anxiolytic phenotypes”
- Also stated in: § Abstract · plain
“20 Hz photostimulation in VgatBNSTv→VTA::ChR2 mice resulted in a significant place preference”
- Also stated in: § Abstract · plain
“VgatBNSTv→VTA::ChR2 mice readily nose poked to receive photostimulation”
§ Distinct extended amygdala circuits for divergent motivational states > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Abstract · plain
- It may state two separate claims as one. 9
- Probably not a substantial claim. 19
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“photostimulation of the CaMKIIaBNSTv→VTA pathway produced both glutamatergic and γ-aminobutyric acid (GABAergic) currents in VTA neurons (Supplementary Fig. 4), demonstrating that neurochemically distinct BNSTv neurons project to the VTA.”
§ Distinct extended amygdala circuits for divergent motivational states > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“photostimulation of ChR2-containing fibers originating from Vglut2 (Vglut2BNSTv→VTA::ChR2) or Vgat (VgatBNSTv→VTA::ChR2) expressing BNSTv neurons produced excitatory or inhibitory postsynaptic currents respectively”
§ Distinct extended amygdala circuits for divergent motivational states > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, data collected during these time epochs were excluded from analysis.”
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > In vivo electrophysiology
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“into the VTA in a counter balanced design (all drugs from Tocris).”
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > Intra-VTA injection of antagonists and photostimulation of Vglut2BNSTv→VTA::ChR2 and VgatBNSTv→VTA::ChR2 projections during real-time place preference
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these results show that reward-related responses to VgatBNSTv→VTA activation are recapitulated by directly inhibiting VgatVTA neurons, thus providing a circuit mechanism for the VgatBNSTv→VTA pathway to regulate motivated behavior.”
§ Distinct extended amygdala circuits for divergent motivational states > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Briefly, discrimination of individual units was performed offline using principal component analysis to separate individual units from the same electrode. In addition, auto- and cross-correlograms, firing characteristics, and inter-spike interval distributions were examined to ensure units were well-isolated.”
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > In vivo electrophysiology
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Placements of recording electrode tips within the BNSTv and optical fibers within the VTA were verified with histological examination of brain tissue following the experiments.”
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > In vivo anesthetized electrophysiology
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“This represents an approximate loss of 0.8 – 1.66% of the collected data during the foot-shock session.”
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > In vivo electrophysiology
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“During the time epoch surrounding the individual delivered foot shocks, large shock artifact were readily apparent.”
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > In vivo electrophysiology
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Resulting data was binned in 30 s epochs in order to minimize the skewing of our results due to data lost by the shock artifacts.”
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > In vivo electrophysiology
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Electrical stimulation of the BNST produces both excitatory and inhibitory responses in VTA neurons in vivo6 implying that distinct subcircuits may exist.”
§ Distinct extended amygdala circuits for divergent motivational states > Abstract
What the sources say
- Not checked yetcites [6] Georges, F. & Aston-Jones, G. Potent regulation of midbrain dopamine neurons by the bed nucleus of the stria terminalis. J. Neurosci. 21, RC160 (2001) source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“BNSTv neurons were classified as antidromic-responsive, if the following 3 criteria were met: 1) stable antidromic spike latency (< 0.2 ms), 2) ability to respond reliably to high frequency photostimulation, 3) collision between orthodromic- and antidromic-evoked spikes.”
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > In vivo anesthetized electrophysiology
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Neuronal units were included in the data if the signal-to-noise ratio was high, and the mean firing rate was between 0.5 – 25 Hz during baseline recording periods.”
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > In vivo electrophysiology
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Mice had 2 days off between each VTA microinjection.”
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > Intra-VTA injection of antagonists and photostimulation of Vglut2BNSTv→VTA::ChR2 and VgatBNSTv→VTA::ChR2 projections during real-time place preference
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, recording sites was verified histologically using electrolytic lesions at 200 µA for 5 s.”
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > In vivo electrophysiology
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“neuronal firing responses in the 500 – 1000 ms following foot shock onset could not be reliably quantified”
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > In vivo electrophysiology
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All mice were infused at a rate of 0.1 µl per minute. The injector remained in place for approximately 2 min following infusion to ensure proper diffusion of drug into the VTA.”
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > Intra-VTA injection of antagonists and photostimulation of Vglut2BNSTv→VTA::ChR2 and VgatBNSTv→VTA::ChR2 projections during real-time place preference
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Recorded BNSTv units were classified as light-responsive, and thus VTA-projecting, if they met both of the following two criteria. 1) The latency of the first spike after light stimulation onset was less than 20 ms for ≥ 20% of the trials. 2) Light-evoked and spontaneous waveform shapes had a correlation coefficient of > 0.90.”
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > In vivo electrophysiology
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Neural activity was recorded from the same mice during the cue exposure, foot shock, and cue re-exposure sessions, therefore we were able to reliably record activity from the same population of neurons during each of the three sessions.”
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > In vivo electrophysiology
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, timestamp data to signify the start and end of foot-shock sessions, and the delivery of light pulses to optical fibers was synchronized with electrophysiological data.”
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > In vivo electrophysiology
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Following the 1 day 20 Hz training session, mice were run daily at each photostimulation frequency (1, 5, 10, 20, 40 Hz) in a counter-balanced design.”
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > Optical self-stimulation of VgatBNSTv→VTA::ChR2 projections
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What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“While these were easily isolated and excluded from the analyzed waveform data using offline spike sorting”
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > In vivo electrophysiology
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The injector needle (33 gauge steel tube, McMasters-Carr) extended approximately 1 mm past the cannula to ensure drug delivery 0.5 mm below the optical fiber.”
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > Intra-VTA injection of antagonists and photostimulation of Vglut2BNSTv→VTA::ChR2 and VgatBNSTv→VTA::ChR2 projections during real-time place preference
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Once stable nose-poking behavior for 15% sucrose was observed (approx. 100 active nose pokes on at least 2 consecutive days), all mice received constant 20 Hz photostimulation during the entire 30 min sucrose session.”
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > Photostimulation of Vglut2BNSTv→VTA::ChR2 projections during sucrose self-administration
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“This is supported by optogenetic studies showing the projection-specific effects of BNST neurons on behavior (87–90).”
From Sexual differentiation of neural mechanisms of stress sensitivity during puberty (2023) · cites this paper as [89]
In the citing paper
“Moreover, individual subregions of the BNST have been shown to differentially regulate separable features of the anxiety phenotype31,85 (Fig. 3).”
From Resolving the neural circuits of anxiety (2015) · cites this paper as [85]
In the citing paper
“activity in glutamatergic ventral BNST neurons projecting to the VTA produces anxiety-like behaviors, whereas GABAergic neurons in the ventral BNST exert anxiolysis via a parallel pathway85.”
From Resolving the neural circuits of anxiety (2015) · cites this paper as [85]
In the citing paper
“It has recently been shown that the BNST contains distinct anxiogenic and anxiolytic GABAergic neuronal subsets with unique patterns of long-range connections (Jennings et al., 2013; Kim et al., 2013).”
From Control of Stress-Induced Persistent Anxiety by an Extra-Amygdala Septohypothalamic Circuit (2014) · cites this paper as Jennings et al., 2013
In the citing paper
“Our results provide further evidence of the importance of long-range GABAergic projection neurons in the control of anxiety (Jennings et al., 2013; Kim et al., 2013).”
From Control of Stress-Induced Persistent Anxiety by an Extra-Amygdala Septohypothalamic Circuit (2014) · cites this paper as Jennings et al., 2013
In the citing paper
“In contrast, photostimulation of glutamatergic projections from ventral BNST to the ventral tegmental area (VTA) (Jennings et al., 2013) was sufficient to induce a persistent elevation in anxiety.”
From Control of Stress-Induced Persistent Anxiety by an Extra-Amygdala Septohypothalamic Circuit (2014) · cites this paper as Jennings et al., 2013
In the citing paper
“Notably, BNST neurons have been shown to inhibit dopamine neurons involved in conventional reward processing by activating local GABAergic neurons63–65, suggesting that anxiety-related circuits may interfere with appetitive learning and behavior.”
From Dopamine dynamics as a regulatory mechanism for shifting between defensive and reward-seeking behaviors (2026) · cites this paper as [63]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Recording electrode differs from the stated requirement for all in vivo experiments
MinorThe methods say mice in all in vivo electrophysiology experiments received a 16-wire array, whereas the anesthetized in vivo electrophysiology procedure describes recording with a glass electrode.
“For all in vivo electrophysiology experiments, mice were implanted with a 16-wire (4 × 4 configuration, wire diameter∼30µm) tungsten multielectrode array (MEA)”
“Extracellular neural activity was recorded using a glass recording electrode (5 − 10 MΩ: and filled with 0.5 M NaCl).”
Injection laterality differs for an in vivo electrophysiology experiment
MinorThe methods say all in vivo electrophysiology mice received unilateral BNSTv injections, but the anesthetized in vivo electrophysiology procedure specifies bilateral injections.
“For all in vivo electrophysiology experiments, male mice were unilaterally injected with 0.5 µl of purified and concentrated adeno-associated virus (AAV)”
“C57BL/6J mice were bilaterally injected with 0.3 µl of AAV5-CaMKIIa-ChR2-eYFP into the BNSTv.”
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“Recorded vBNST units were classified as light-responsive, and thus VTA-projecting, if they met both of the following two criteria: (1) the latency of the first spike after light stimulation onset was less than 20ms for$20% of the trials; and (2) light-evoked and spontaneous waveform shapes had a correlation coefficien…”
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Dopamine neurons modulate neural encoding and expression of depression-related behaviour
Tye, K. M., Mirzabekov, J. J., Warden, M. R., Ferenczi, E. A., Tsai, H.-C., Finkelstein, J., Kim, S.-Y., Adhikari, A., Thompson, K. R., Andalman, A. S., et al. (2013) · Nature · doi:10.1038/nature11740 · Cited by 1,073
Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking
Stuber, G. D., Sparta, D. R., Stamatakis, A. M., van Leeuwen, W. A., Hardjoprajitno, J. E., Cho, S., Tye, K. M., Kempadoo, K. A., Zhang, F., Deisseroth, K., et al. (2011) · Nature · doi:10.1038/nature10194 · Cited by 878
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Sparta, D. R., Hovelsø, N., Mason, A. O., Kantak, P. A., Ung, R. L., Decot, H., & Stuber, G. D. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.0235-13.2014 · Cited by 128
“Brain slice preparation and general methods for patch-clamp electrophysiology were conducted as described previously (Stamatakis and Stuber, 2012; van Zessen et al., 2012; Jennings et al., 2013).”
MethodSelf-citationIkemoto, S., & Bonci, A. (2013) · Neuropharmacology · doi:10.1016/j.neuropharm.2013.04.031 · Cited by 129
“Recent optogenetic study suggests that the afferent inputs coming from the lateral habenula or bed nucleus of stria terminalis provide aversive signals to the RMTg and VTA by exciting local GABA neurons (Jennings et al., 2013; Jhou et al., 2013; Lammel et al., 2012; Stamatakis and Stuber, 2012).”
BackgroundChen, Y.-H., Wu, J., Hu, N.-Y., Zhuang, J.-P., Li, W., Zhang, S.-R., Li, X.-W., Yang, J., & Gao, T. (2021) · Journal of Clinical Investigation · doi:10.1172/jci145692 · Cited by 126
“Particular intrinsic, homeostatic, or counterbalancing elements orchestrate behavioral states in animals with highly diverse repertoires of internal states and adaptations to the environment (43, 60, 61).”
BackgroundRewarding Effects of Optical Stimulation of Ventral Tegmental Area Glutamatergic Neurons
Wang, H., Qi, J., Zhang, S. S., Wang, H., & Morales, M. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.3428-15.2015 · Cited by 125
“In contrast, activation of VTA GABAergic neurons is aversive (Tan et al., 2012), whereas their inhibition is rewarding (Jennings et al., 2013).”
BackgroundA Paranigral VTA Nociceptin Circuit that Constrains Motivation for Reward
Parker, K. E., Pedersen, C. E., Gomez, A. M., Spangler, S. M., Walicki, M. C., Feng, S., Stewart, S., Otis, J. M., Al‐Hasani, R., McCall, J. G., et al. (2019) · Cell · doi:10.1016/j.cell.2019.06.034 · Cited by 113
Self-citationThe role of Neuropeptide Y in fear conditioning and extinction
Tasan, R. O., Verma, D., Wood, J. C., Lach, G., Hörmer, B. A., de Lima, T. C. M., Herzog, H., & Sperk, G. (2015) · Neuropeptides · doi:10.1016/j.npep.2015.09.007 · Cited by 121
Neumann, W., Huebl, J., Brücke, C., Gabriëls, L. A., Bajbouj, M., Merkl, A., Schneider, G.-H., Nuttin, B., Brown, P., & Kühn, A. A. (2014) · Molecular Psychiatry · doi:10.1038/mp.2014.2 · Cited by 119
Role of the endocannabinoid system in drug addiction
Manzanares, J., Cabañero, D., Puente, N., García‐Gutiérrez, M. S., Grandes, P., & Maldonado, R. J. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.09.013 · Cited by 118
De Bundel, D., Zussy, C., Espallergues, J., Gerfen, C. R., Girault, J.-A., & Valjent, E. (2016) · Molecular Psychiatry · doi:10.1038/mp.2015.210 · Cited by 112
Williamson, R. S., & Polley, D. B. (2019) · eLife · doi:10.7554/elife.42974 · Cited by 110
Bed nucleus of the stria terminalis regulates fear to unpredictable threat signals
Goode, T. D., Ressler, R. L., Acca, G. M., Miles, O. W., & Maren, S. (2019) · eLife · doi:10.7554/elife.46525 · Cited by 120
Brain Reward Circuits in Morphine Addiction
Kim, J., Ham, S., Hong, H., Moon, C., & Im, H. (2016) · Molecules and Cells · doi:10.14348/molcells.2016.0137 · Cited by 117
“To support this result, more recent studies also found that optogenetic or pharmacological activation of GABAergic projections from the BNST to the VTA can inhibit VTA dopaminergic transmission (Jennings et al., 2013; van Zessen et al., 2012).”
BackgroundResultThe intersection of stress and reward: BNST modulation of aversive and appetitive states
Ch’ng, S. S., Fu, J., Brown, R. M., McDougall, S. J., & Lawrence, A. J. (2018) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2018.01.005 · Cited by 118
Optogenetic Modulation of Neural Circuits that Underlie Reward Seeking
Stuber, G. D., Britt, J. P., & Bonci, A. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.11.010 · Cited by 124
“While electrical stimulation of the BNST produces both excitatory and inhibitory responses in the VTA (Georges and Aston-Jones, 2001), we have recently demonstrated that the BNST sends a mixed glutamatergic and GABAergic projection that preferentially inneverates non-DAergic neurons in the VTA (Jennings et al., 2013).”
BackgroundSelf-citationBoender, A. J., de Jong, J. W., Boekhoudt, L., Luijendijk, M. C. M., Plasse, G., & Adan, R. A. H. (2014) · PLoS ONE · doi:10.1371/journal.pone.0095392 · Cited by 107
“The combination of optogenetic and designer receptor exclusively activated by designer drugs (DREADD) technologies with CRE-mediated homologous recombination enables specific targeting and manipulation of neural pathways and has improved our understanding of how the activity of specific neuronal pathways can act as de…”
BackgroundSteinman, M. Q., Duque-Wilckens, N., & Trainor, B. C. (2019) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.10.008 · Cited by 105
“Here, we focused on OT action within the mesolimbic dopamine system and extended amygdala, networks that have strong functional connections (77,140).”
Neuropeptide Regulation of Signaling and Behavior in the BNST
Kash, T. L., Pleil, K. E., Marcinkiewcz, C. A., Lowery‐Gionta, E. G., Crowley, N. A., Mazzone, C. M., Sugam, J. A., Hardaway, J. A., & McElligott, Z. A. (2014) · Molecules and Cells · doi:10.14348/molcells.2015.2261 · Cited by 105
Self-citationDoes the kappa opioid receptor system contribute to pain aversion?
Cahill, C. M., Taylor, A. M. W., Cook, C., Ong, E., Morón, J. A., & Evans, C. J. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00253 · Cited by 105
Identification of a Corticohabenular Circuit Regulating Socially Directed Behavior
Benekareddy, M., Stachniak, T. J., Bruns, A., Knoflach, F., von Kienlin, M., Künnecke, B., & Ghosh, A. (2017) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.10.032 · Cited by 103
“Possible alternative pathways for a prefrontal control over midbrain circuitry include parallel circuits from the PFC–bed nucleus of the stria terminalis, PFC–septum, or PFC–lateral hypothalamus, all of which could potentially gate contextual information to VTA neurons (40,41).”
BackgroundRDoC-based categorization of amygdala functions and its implications in autism
Hennessey, T., Andari, E., & Rainnie, D. G. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.04.007 · Cited by 107
Priddy, S. E., Howard, M. O., Hanley, A. W., Riquino, M. R., Friberg-Felsted, K., & Garland, E. L. (2018) · Substance Abuse and Rehabilitation · doi:10.2147/sar.s145201 · Cited by 101
“56,57 Gradually, a person may become dependent on substances as a means of regulating the dysphoria and anxiety stemming from increased stress reactivity, ensnaring them deeper into the cycle of addiction.”
BackgroundWenzel, J. M., Oleson, E. B., Gove, W. N., Cole, A. B., Gyawali, U., Dantrassy, H. M., Bluett, R. J., Dryanovski, D. I., Stuber, G. D., Deisseroth, K. A., et al. (2018) · Current Biology · doi:10.1016/j.cub.2018.03.037 · Cited by 102
Self-citationCortico-Limbic Interactions Mediate Adaptive and Maladaptive Responses Relevant to Psychopathology
Kovner, R., Oler, J. A., & Kalin, N. H. (2019) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2019.19101064 · Cited by 111
Anxiety and Nicotine Dependence: Emerging Role of the Habenulo-Interpeduncular Axis
Molas, S., DeGroot, S. R., Zhao-Shea, R., & Tapper, A. R. (2016) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.11.001 · Cited by 109
“BNST afferents in the VTA promote anxiogenic behavior when Glu is released and anxiolytic behavior when GABA is released via optogenetic stimulation [58].”
BackgroundResting state connectivity of the bed nucleus of the stria terminalis at ultra‐high field
Torrisi, S., O’Connell, K., Davis, A., Reynolds, R. C., Balderston, N. L., Fudge, J. L., Grillon, C., & Ernst, M. (2015) · Human Brain Mapping · doi:10.1002/hbm.22899 · Cited by 104
“…in the autonomic arousal and sustained nature of anxiety [Davis et al., 2010; Johansen, 2013; Walker et al., 2003] and complex motivational responses, including the withdrawal and craving stages of addiction disorders [Jennings et al., 2014; Koob and Volkow, 2009; Silberman and Winder, 2013].”
BackgroundA comparison of neural responses to appetitive and aversive stimuli in humans and other mammals
Hayes, D. J., Duncan, N. W., Xu, J., & Northoff, G. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2014.06.018 · Cited by 102
Illuminating circuitry relevant to psychiatric disorders with optogenetics
Steinberg, E. E., Christoffel, D. J., Deisseroth, K., & Malenka, R. C. (2015) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2014.08.004 · Cited by 92
Persistent Adaptations in Afferents to Ventral Tegmental Dopamine Neurons after Opiate Withdrawal
Kaufling, J., & Aston‐Jones, G. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.0715-15.2015 · Cited by 89
“…and Pickel, 1992; Murase et al., 1993; Karreman and Moghaddam, 1996; Harden et al., 1998), the bed nucleus of the stria terminalis (Georges and Aston-Jones, 2001; Georges and Aston-Jones, 2002; Jennings et al., 2013), and the pedunculopontine nucleus (Charara et al., 1996; Floresco et al., 2003).”
BackgroundVranjkovic, O., Pina, M., Kash, T. L., & Winder, D. G. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.03.028 · Cited by 79
“The bed nucleus of the stria terminalis (BNST) was first anatomically defined in 1923 by Johnston, who described the structure as a “band or ridge of gray matter lying medial to the caudate nucleus” (Johnston, 1923, see Fig.”
BackgroundSelf-citationModulation of anxiety and fear via distinct intrahippocampal circuits
Engin, E., Smith, K. S., Gao, Y., Nagy, D., Foster, R. A., Tsvetkov, E., Keist, R., Crestani, F., Fritschy, J.-M., Bolshakov, V. Y., et al. (2016) · eLife · doi:10.7554/elife.14120 · Cited by 91
“Anxiety and fear are regulated by overlapping but somewhat distinct circuits in the brain (e.g., Jennings et al., 2013, Kheirbek et al., 2013, Botta et al., 2015).”
BackgroundSilberman, Y., & Winder, D. G. (2013) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2013.00042 · Cited by 96
“This is an important consideration as the dorsal BNST, which has a high proportion of GABAergic interneurons, sends afferents to the ventral BNST, which has a higher proportion of projection neurons (Dong et al., 2001).”
BackgroundInfluentialChen, Y., Molet, J., Gunn, B. G., Ressler, K. J., & Baram, T. Z. (2015) · Endocrinology · doi:10.1210/en.2015-1673 · Cited by 87
“These combined methods have yielded a large body of innovative discoveries in brain connectivity and in the contributions of specific neuronal populations, and of molecules produced in specific regions, to crucial brain functions, including feeding (1), reward and addiction (2, 3), memory (4), and depression (5).”
BackgroundKaras, P. J., Lee, S., Shahed, J. J., Goodman, W. K., Viswanathan, A., & Sheth, S. A. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00998 · Cited by 89
“A study of selective optogenetic stimulation of excitatory or inhibitory BNST inputs to the ventral tegmental area produced anxiogenic or anxiolytic behavior, respectively (Jennings et al., 2013), and stimulation of excitatory BNST inputs to the NAc facilitated reward-seeking behavior in rodent models (Jennings et al.”
BackgroundYamauchi, N., Sato, K., Sato, K., Murakawa, S., Hamasaki, Y., Nomura, H., Amano, T., & Minami, M. (2022) · Science Advances · doi:10.1126/sciadv.abj5586 · Cited by 90
“To determine whether ovBNSTCART neurons make inhibitory synapses onto other output neurons regulating anxiety-like behavior, we examined the effect of optogenetic stimulation of ovBNSTCART neurons on the inhibitory inputs recorded from VTA-projecting BNST neurons, the activation of which was reported to exert an anxio…”
BackgroundThe Role of the Rodent Insula in Anxiety
Méndez-Ruette, M., Linsambarth, S., Moraga‐Amaro, R., Quintana-Donoso, D., Méndez, L., Tamburini, G., Cornejo, F., Torres, R. F., & Stehberg, J. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00330 · Cited by 96
“The insula and the amygdala are also reciprocally connected with the ventral tegmental area, which releases dopamine and its activation induces anxiolytic effects (Jennings et al., 2013).”
BackgroundMicrofluidic neural probes: in vivo tools for advancing neuroscience
Sim, J. Y., Haney, M. P., Park, S. I., McCall, J. G., & Jeong, J. (2017) · Lab on a Chip · doi:10.1039/c7lc00103g · Cited by 87
Krüger, O., Shiozawa, T., Kreifelts, B., Scheffler, K., & Ethofer, T. (2015) · Cortex · doi:10.1016/j.cortex.2015.02.007 · Cited by 81
“Furthermore, these connections have been implicated in the context of rewarding versus aversive motivation (Jennings et al., 2013) which are subserved by mainly monoaminergic projections (Shin et al., 2008) that modulate the BNST's influence on the HPA and withdrawalrelated behavior (Aston-Jones,…”
BackgroundVentral tegmental area astrocytes orchestrate avoidance and approach behavior
Gomez, J. A., Perkins, J., Beaudoin, G. M. J., Cook, N. B., Quraishi, S., Szoeke, E. A., Kannan, T., Tschumi, C. W., Wanat, M. J., Maroof, A. M., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09131-y · Cited by 81
Mazzone, C. M., Pati, D., Michaelides, M., DiBerto, J. F., Fox, J. H., Tipton, G., Anderson, C., Duffy, K. A., McKlveen, J. M., Hardaway, J. A., et al. (2016) · Molecular Psychiatry · doi:10.1038/mp.2016.218 · Cited by 82
“However, optogenetic activation of discrete BNST outputs can also reduce anxiety-like behavior, highlighting how BNST stimulation can have opposing regulatory processes (15,16).”
InfluentialSelf-citationc-Fos mapping of brain regions activated by multi-modal and electric foot shock stress
Lin, X., Itoga, C. A., Taha, S. A., Li, M. H., Chen, R., Sami, K., Berton, F., Francesconi, W., & Xu, X. (2018) · Neurobiology of Stress · doi:10.1016/j.ynstr.2018.02.001 · Cited by 92
Henckens, M. J. A. G., Printz, Y., Shamgar, U., Dine, J., Lebow, M., Drori, Y., Kühne, C., Kolarz, A., Eder, M., Deussing, J. M., et al. (2016) · Molecular Psychiatry · doi:10.1038/mp.2016.133 · Cited by 83
Vagal Interoceptive Modulation of Motivated Behavior
Maniscalco, J. W., & Rinaman, L. (2018) · Physiology · doi:10.1152/physiol.00036.2017 · Cited by 83
Non-pharmacological factors that determine drug use and addiction
Ahmed, S. H., Badiani, A., Miczek, K. A., & Müller, C. P. (2018) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2018.08.015 · Cited by 85
“Activation of both CRFR1 and CRFR2 in the VTA during social defeat stress is necessary for the induction and later expression of behavioral and neural cross-sensitization to cocaine and escalated cocaine self-administration in a 24-h “binge” (Boyson et al. 2014).”
BackgroundInfluentialZona incerta subpopulations differentially encode and modulate anxiety
Li, Z., Rizzi, G., & Tan, K. R. (2021) · Science Advances · doi:10.1126/sciadv.abf6709 · Cited by 80
Partridge, J. G., Forcelli, P. A., Luo, R., Cashdan, J. M., Schulkin, J., Valentino, R. J., & Vicini, S. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.03.029 · Cited by 81
“In addition, the BnST sends both 16 GABAergic and glutamatergic projections to the ventral tegmental area (VTA) and other 17 areas involved in the regulation of anxiety (Jennings et al., 2013; Johansen, 2013; 18 Johansen, 2013).”
Circadian regulation of membrane physiology in neural oscillators throughout the brain
Paul, J. R., Davis, J. A., Goode, L. K., Becker, B., Fusilier, A. R., Meador-Woodruff, A., & Gamble, K. L. (2019) · European Journal of Neuroscience · doi:10.1111/ejn.14343 · Cited by 81
“Given that optogenetic stimulation of BNST neurons can be anxiolytic versus anxiogenic, depending on whether respective inhibitory or excitatory BNST neurons are targeted (Jennings et al., 2013), future studies are necessary to determine whether increased firing during the day corresponds to enhanced fear memory at th…”
BackgroundCurrent Understanding of the Neural Circuitry in the Comorbidity of Chronic Pain and Anxiety
Chen, T., Wang, J., Wang, Y.-Q., & Chu, Y. (2022) · Neural Plasticity · doi:10.1155/2022/4217593 · Cited by 80
“Photostimulation of the vBNST glutamatergic projections (vBNST Glu+ ) to the VTA results in aversive and anxiogenic behaviors, while stimulating the GABAergic vBNST (vBNST GABA+ ) projections to the VTA results in rewarding and anxiolytic behaviors [85].”
Local and regional heterogeneity underlying hippocampal modulation of cognition and mood
Tannenholz, L., Jimenez, J., & Kheirbek, M. A. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00147 · Cited by 83
Fiore, N. T., & Austin, P. J. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.04.012 · Cited by 80
Functions of medial hypothalamic and mesolimbic dopamine circuitries in aggression
Yamaguchi, T., & Lin, D. (2018) · Current Opinion in Behavioral Sciences · doi:10.1016/j.cobeha.2018.06.011 · Cited by 77
Oler, J. A., Tromp, D., Fox, A. S., Kovner, R., Davidson, R. J., Alexander, A. L., McFarlin, D. R., Birn, R. M., Berg, B. E., deCampo, D. M., et al. (2016) · Brain Structure and Function · doi:10.1007/s00429-016-1198-9 · Cited by 82
“Evidence from rats and monkeys displaying anxiety-like behaviors (Duvarci et al. 2009; Fox et al. 2008; Jennings et al. 2013; Kalin et al. 2005; Kim et al. 2013), as well as from humans (Alvarez et al.”
Divergent projections of the prelimbic cortex bidirectionally regulate active avoidance
Diehl, M. M., Iravedra-García, J. M., Morán-Sierra, J., Rojas-Bowe, G., Gonzalez-Diaz, F. N., Valentín-Valentín, V. P., & Quirk, G. J. (2020) · eLife · doi:10.7554/elife.59281 · Cited by 80
Neuronal correlates of fear conditioning in the bed nucleus of the stria terminalisPreprint
Haufler, D., Nagy, F. Z., & Paré, D. (2013) · Learning & Memory · doi:10.1101/lm.031799.113 · Cited by 81
“(Jennings et al. 2013) revealed that BNST is functionally heterogeneous.”
Distinguishing externally from saccade-induced motion in visual cortex
Miura, S. K., & Scanziani, M. (2022) · Nature · doi:10.1038/s41586-022-05196-w · Cited by 77
Prefrontal modulation of anxiety through a lens of noradrenergic signaling
Bouras, N. N., Mack, N. R., & Gao, W. (2023) · Frontiers in Systems Neuroscience · doi:10.3389/fnsys.2023.1173326 · Cited by 88
“These subregions are seemingly distinct and, at times, opposing in functionality (Jennings et al., 2013; Kim et al., 2013).”
BackgroundHartmann, J., Dedic, N., Pöhlmann, M. L., Häusl, A. S., Karst, H., Engelhardt, C., Westerholz, S., Wagner, K. V., Labermaier, C., Hoeijmakers, L., et al. (2016) · Molecular Psychiatry · doi:10.1038/mp.2016.87 · Cited by 75
Rodriguez-Romaguera, J., Ung, R. L., Nomura, H., Otis, J. M., Basiri, M. L., Namboodiri, V. M. K., Zhu, X., Robinson, J. E., van den Munkhof, H. E., McHenry, J. A., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108362 · Cited by 75
“…other adBNST output regions, including the arcuate nucleus (ARC), lateral hypothalamic area (LHA), ventromedial hypothalamus (VMH), parabrachial nucleus (PB), and periaqueductal gray (PAG) (Figures 5D and 5E) (Calhoon and Tye, 2015; Jennings et al., 2013a; Kim et al., 2013; Lebow and Chen, 2016).”
InfluentialSelf-citationMillan, E. Z., Kim, H. A., & Janak, P. H. (2017) · Neuroscience · doi:10.1016/j.neuroscience.2017.07.044 · Cited by 78
“Neuroscience (2017), http://dx will be useful for parsing the specific role of the BLA– AcbSh pathway on shaping consummatory responses, particularly since antidromic activation can occur following pathway optical stimulation (Jennings et al., 2013) and could potentially affect collateral targets, including to the med…”
Brain activation induced by chronic psychosocial stress in mice
Laine, M. A., Sokolowska, E., Dudek, M., Callan, S., Hyytiä, P., & Hovatta, I. (2017) · Scientific Reports · doi:10.1038/s41598-017-15422-5 · Cited by 78
Sparta, D. R., Smithuis, J., Stamatakis, A. M., Jennings, J. H., Kantak, P. A., Ung, R. L., & Stuber, G. D. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00129 · Cited by 75
“PATCH-CLAMP ELECTROPHYSIOLOGY Brain slice preparation and general methods for patchclamp electrophysiology were conducted as previously described (Stamatakis and Stuber, 2012; van Zessen et al., 2012; Jennings et al., 2013).”
BackgroundMethodInfluentialSelf-citationAdvances in optogenetic and chemogenetic methods to study brain circuits in non-human primates
Galván, A., Caiola, M. J., & Albaugh, D. L. (2017) · Journal of Neural Transmission · doi:10.1007/s00702-017-1697-8 · Cited by 75
“Although increasingly used in rodent studies (Beyeler et al. 2016; Jennings et al. 2013; Nieh et al. 2015), phototagging has, to date, played a minimal role in neurophysiology studies of NHPs.”
MethodAmygdala substructure volumes in Major Depressive Disorder
Roddy, D. W., Kelly, J. R., Farrell, C. M., Doolin, K., Román, E., Nasa, A., Frodl, T., Harkin, A., O’Mara, S. M., O’Hanlon, E., et al. (2021) · NeuroImage Clinical · doi:10.1016/j.nicl.2021.102781 · Cited by 79
“Projections from the bed nuclei of stria terminalis to the lateral hypothalamus and the ventral tegmental area have been shown to modulate divergent emotional/physiological states (Giardino et al., 2018; Jennings et al., 2013).”
BackgroundDabrowska, J., Martinon, D., Moaddab, M., & Rainnie, D. G. (2016) · Journal of Neuroendocrinology · doi:10.1111/jne.12442 · Cited by 75
“In the last decade, interest in the role of the BNST’s modulation of distinct features of anxiety (28) and divergent motivational states (29) has achieved circuit specificity with neuronal-specific promoters or promoters for GABA-ergic or glutamatergic markers to control BNST activity using opto-or…”
BackgroundSerotonin inputs to the dorsal BNST modulate anxiety in a 5-HT1A receptor-dependent manner
Garcia‐García, Á. L., Canetta, S., Stujenske, J. M., Burghardt, N. S., Ansorge, M. S., Dranovsky, A., & Leonardo, E. D. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.165 · Cited by 73
Central amygdala circuits in valence and salience processing
Kong, M.-S., & Zweifel, L. S. (2021) · Behavioural Brain Research · doi:10.1016/j.bbr.2021.113355 · Cited by 86
Antagonistic circuits mediating infanticide and maternal care in female mice
Mei, L., Yan, R., Yin, L., Sullivan, R. M., & Lin, D. (2023) · Nature · doi:10.1038/s41586-023-06147-9 · Cited by 73
Vranjkovic, O., Gasser, P. J., Gerndt, C. H., Baker, D. L., & Mantsch, J. R. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.0680-14.2014 · Cited by 73
“Both GABAergic and glutamatergic projections from the BNST to the VTA have been identified (Georges and Aston-Jones, 2001, 2002; Kudo et al., 2012; Jennings et al., 2013).”
BackgroundRichter, C., & Tan, X. (2014) · Hearing Research · doi:10.1016/j.heares.2014.03.008 · Cited by 73
“Another study targeted the bed nucleus of the stria terminalis, the region modulating fear and anxiety, which also projected to VTA, using the same optogenetic construct (Jennings et al., 2013).”
Paretkar, T., & Dimitrov, E. L. (2018) · Neuroscience · doi:10.1016/j.neuroscience.2018.08.019 · Cited by 73
Primate optogenetics: Progress and prognosis
El-Shamayleh, Y., & Horwitz, G. D. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1902284116 · Cited by 78
Optogenetic dissection of amygdala functioning
LaLumiere, R. T. (2014) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2014.00107 · Cited by 79
“…propagation of action potentials back to the BLA, largely eliminating the concern that such propagation could be responsible for the behavioral effect, though it is clear that optical stimulation of axon terminals can produce reliable antidromic propagation to cell bodies (Jennings et al., 2013).”
BackgroundOptogenetic strategies to investigate neural circuitry engaged by stress
Sparta, D. R., Jennings, J. H., Ung, R. L., & Stuber, G. D. (2013) · Behavioural Brain Research · doi:10.1016/j.bbr.2013.05.007 · Cited by 72
Self-citationLee, K. M., Coehlo, M. A., Solton, N. R., & Szumlinski, K. K. (2017) · Frontiers in Psychology · doi:10.3389/fpsyg.2017.01128 · Cited by 72
“Studies have revealed persistent alcohol-induced neurobiological changes within the extended amygdala – the subcortical macrostructure integrally involved in governing diverse emotional states (Alheid, 2003; Jennings et al., 2013; Shackman and Fox, 2016).”
BackgroundDeGroot, S. R., Zhao-Shea, R., Chung, L., Klenowski, P. M., Sun, F., Molas, S., Gardner, P. D., Li, Y., & Tapper, A. R. (2020) · Biological Psychiatry · doi:10.1016/j.biopsych.2020.06.018 · Cited by 87
Coordination of social behaviors by the bed nucleus of the stria terminalis
Flanigan, M. E., & Kash, T. L. (2022) · European Journal of Neuroscience · doi:10.1111/ejn.14991 · Cited by 71
“Although the BNST largely promotes negative affect and aversion-related behaviors, distinct BNST cell types and circuits can in fact drive reward-related behaviors (Jennings et al., 2013).”
BackgroundSelf-citationNguyen, A. Q., Cruz, J. A. D. D., Sun, Y., Holmes, T. C., & Xu, X. (2015) · The Journal of Comparative Neurology · doi:10.1002/cne.23954 · Cited by 70
“These findings provide neuronal makeup differences corroborating the known functional differences of adBNST and vBNST (Dong et al., 2000; Dong and Swanson, 2004; Poulin et al., 2009; Jennings et al., 2013; Kim et al., 2013).”
BackgroundResultInfluentialNeuronal diversity of the amygdala and the bed nucleus of the stria terminalis
Beyeler, A., & Dabrowska, J. (2020) · Handbook of behavioral neuroscience · doi:10.1016/b978-0-12-815134-1.00003-9 · Cited by 74
“Presence of glutamatergic neurons in mouse BNSTVEN has been confirmed in VGLUT2-IRES-Cre mouse (Georges & Aston-Jones, 2002; Gungor, Yamamoto, & Pare, 2018; Jennings et al., 2013) and based on the expression of the excitatory amino acid carrier 1 (EAAC) (Nguyen et al.”
BackgroundCoordination of Brain-Wide Activity Dynamics by Dopaminergic Neurons
Decot, H., Namboodiri, V. M. K., Gao, W., McHenry, J. A., Jennings, J. H., Lee, S., Kantak, P. A., Kao, Y. J., Das, M., Witten, I. B., et al. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2016.151 · Cited by 66
“…ChR2 conjugated to eYFP (ChR2-eYFP), selectively into VTA neurons in transgenic rats that express Cre recombinase under the Neuropsychopharmacology control of the tyrosine hydroxylase (TH) gene promoter (Witten et al, 2011) using established viral procedures (Jennings et al, 2013) (Figure 1a).”
MethodSelf-citationPolter, A. M., Bishop, R. A., Briand, L. A., Graziane, N., Pierce, R. C., & Kauer, J. A. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.04.019 · Cited by 67
“With the field stimulation used in our experiments, we likely are activating a number of inhibitory projections from several regions known to modulate firing and excitability of dopamine neurons (61, 62, 64-66).”
MethodJohnson, S. B., Emmons, E. B., Anderson, R. M., Glanz, R. M., Romig‐Martin, S. A., Narayanan, N. S., LaLumiere, R. T., & Radley, J. J. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.1185-16.2016 · Cited by 71
“, fear, anxiety-like) behaviors (Walker et al., 2003; Davis et al., 2010; Jennings et al., 2013; Kim et al., 2013), although little attention has been given to its capacity to modulate behavioral coping during inescapable challenges.”
BackgroundResultLange, M. D., Daldrup, T., Remmers, F., Szkudlarek, H. J., Lesting, J., Guggenhuber, S., Ruehle, S., Jüngling, K., Seidenbecher, T., Lutz, B., et al. (2016) · Molecular Psychiatry · doi:10.1038/mp.2016.156 · Cited by 66
The fiber-optic imaging and manipulation of neural activity during animal behavior
Miyamoto, D., & Murayama, M. (2015) · Neuroscience Research · doi:10.1016/j.neures.2015.09.004 · Cited by 67
Leptin/LepRb in the Ventral Tegmental Area Mediates Anxiety-Related Behaviors
Liu, J., Guo, M., & Lu, X. (2015) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyv115 · Cited by 68
“Recently, it was demonstrated that stimulation and inhibition of dopamine vs GABA neurons in the VTA affect anxietyrelated behaviors and aversive responses (Tan et al., 2012; van Zessen et al., 2012; Jennings et al., 2013; Danjo et al., 2014).”
BackgroundCell-Specific Targeting of Genetically Encoded Tools for Neuroscience
Sjulson, L., Cassataro, D., Dasgupta, S., & Miesenböck, G. (2016) · Annual Review of Genetics · doi:10.1146/annurev-genet-120215-035011 · Cited by 74
Neuropeptides at the crossroad of fear and hunger: a special focus on neuropeptide Y
Comeras, L. B., Herzog, H., & Tasan, R. O. (2019) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14179 · Cited by 72
Seo, D.-O., Funderburk, S. C., Bhatti, D. L., Motard, L. E., Newbold, D. J., Girven, K. S., McCall, J. G., Krashes, M. J., Sparta, D. R., & Bruchas, M. R. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.1164-16.2016 · Cited by 67
“Brain slice preparation and general methods for patch-clamp electrophysiology were conducted as described previously (Jennings et al., 2013).”
MethodSelf-citationYe, J., & Veinante, P. (2019) · Brain Structure and Function · doi:10.1007/s00429-018-01825-1 · Cited by 68
Toggling between food-seeking and self-preservation behaviors via hypothalamic response networks
Salgado, I. D. A., Li, C., Burnett, C. J., Rodriguez-Gonzalez, S., Becker, J. J., Horvath, A., Earnest, T., Kravitz, A. V., & Krashes, M. J. (2023) · Neuron · doi:10.1016/j.neuron.2023.06.006 · Cited by 61
Stuber, G. D. (2023) · Science · doi:10.1126/science.adh8287 · Cited by 69
Self-citationOptogenetics to study the circuits of fear- and depression-like behaviors: A critical analysis
Belzung, C., Turiault, M., & Griebel, G. (2014) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2014.04.002 · Cited by 65
“anxiogenic-like behaviors Jennings et al. (2013) 50”
InfluentialManual segmentation of the human bed nucleus of the stria terminalis using 3 T MRI
Theiss, J. D., Ridgewell, C., McHugo, M., Heckers, S., & Blackford, J. U. (2016) · NeuroImage · doi:10.1016/j.neuroimage.2016.11.047 · Cited by 64
Extended amygdala-parabrachial circuits alter threat assessment and regulate feeding
Luskin, A. T., Bhatti, D. L., Mulvey, B., Pedersen, C. E., Girven, K. S., Oden-Brunson, H., Kimbell, K., Blackburn, T., Sawyer, A., Gereau, R. W., et al. (2021) · Science Advances · doi:10.1126/sciadv.abd3666 · Cited by 63
“Neurons were photostimulated at 20 Hz, consistent with previously identified firing rates in BNST projection neurons (20).”
MethodNeural Circuit Mechanisms Underlying Emotional Regulation of Homeostatic Feeding
Sweeney, P., & Yang, Y. (2017) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2017.02.006 · Cited by 67
Salimando, G. J., Hyun, M., Boyt, K. M., & Winder, D. G. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.0270-20.2020 · Cited by 63
“…also been implicated in driving emotional behavior, with previous studies reporting that disruptions of inter- and intra-BNST excitatory synaptic function can lead to increases or decreases in anxiety- and depressive-like behaviors (Jennings et al., 2013; Kim et al., 2013; Glangetas et al., 2017).”
ResultWood, J. C., Verma, D., Lach, G., Bonaventure, P., Herzog, H., Sperk, G., & Tasan, R. O. (2015) · Brain Structure and Function · doi:10.1007/s00429-015-1107-7 · Cited by 66
“Thus, fearful situations that strongly activate NPY neurons may cause NPY release and result in a time-lagged but prolonged action of NPY limiting an otherwise excessive fear response (Heilig et al. 1994; Heilig 2004).”
Marcinkiewcz, C. A., Dorrier, C., López, A. J., & Kash, T. L. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.09.003 · Cited by 62
“Interestingly, this vBNST-to-VTA pathway is appetitive and anxiolytic if GABAergic neurons are involved, whereas glutamatergic projections appear to be aversive and anxiogenic (Jennings et al., 2013).”
BackgroundSelf-citationVentral Tegmental Area Afferents and Drug-Dependent Behaviors
Oliva, I., & Wanat, M. J. (2016) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2016.00030 · Cited by 68
“Interesting, glutamate neurons in the BNST also innervate VTA GABA neurons, and activation of these neurons elicits aversive and anxiogenic behaviors (129).”
BackgroundSoden, M. E., Chung, A. S., Cuevas, B., Resnick, J. M., Awatramani, R. B., & Zweifel, L. S. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-0657-z · Cited by 74
Ethanol actions on the ventral tegmental area: novel potential targets on reward pathway neurons
You, C., Vandegrift, B. J., & Brodie, M. S. (2018) · Psychopharmacology · doi:10.1007/s00213-018-4875-y · Cited by 67
“Glutamatergic neurons from the BNST innervate GABA neurons of the VTA to regulate behaviors related to aversion (Jennings et al. 2013).”
BackgroundOptogenetics enlightens neuroscience drug discovery
Song, C., & Knöpfel, T. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2015.15 · Cited by 63
Metadata
- Authors
- Jennings, J. H., Sparta, D. R., Stamatakis, A. M., Ung, R. L., Pleil, K. E., Kash, T. L., & Stuber, G. D.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Stuber, Garret D.
- ORCID
- Venue
- Nature
- Published
- 2013-03-20
- Volume
- 496
- Issue
- 7444
- Pages
- 224-228
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3778934
- OpenAlex
- W2067203693
- Semantic Scholar
- b094f8c7bc24b675130d787985a6c38dc2555363
- Cited by
- 704
- References
- 33
- Citations by year
- 2026: 34 · 2025: 53 · 2024: 30 · 2023: 44 · 2022: 35 · 2021: 65 · 2020: 43 · 2019: 55 · 2018: 57 · 2017: 55 · 2016: 78 · 2015: 66 · 2014: 58 · 2013: 29
- FWCI
- 37.77
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Foundation for the National Institutes of Health
- Whitehall Foundation
- National Institute on Alcohol Abuse and Alcoholism (F32AA018610, AA011605, AA 007573, F32AA021043, AA018610, AA021043, P60AA011605, T32AA007573)
- National Institute on Drug Abuse (F31DA034472, R01DA032750, DA034472, DA029325, R21DA029325, DA032750, R37DA032750)
- National Institute of Neurological Disorders and Stroke (P30NS045892, NS 007431, T32NS007431)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- bed nucleus of the stria terminalis, ventral tegmental area, extended amygdala, glutamatergic projections, GABAergic projections, anxiety, reward, aversion, motivational states, depression, channelrhodopsin-2, aversive stimuli
- MeSH terms
- Channelrhodopsins, Amygdala, Animals, Anxiety, Avoidance Learning, Behavior, Animal, Cues, Electroshock, Glutamine, Male, Mice, Inbred C57BL, Motivation, Phenotype, Reward, Septal Nuclei, Ventral Tegmental Area, Mice, GABAergic Neurons, Optogenetics
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