The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index; none of the 1 sources its claims cite is checked for support yet.
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.
Overview
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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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21 Own method · 15 Own result · 8 Own interpretation · 1 Not checked yet
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
plaindirect- Asserted: passes — The authors put it forward as true.
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- 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
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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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
“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
plaindirect- Asserted: passes — The authors put it forward as true.
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- 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
plaindirect- Asserted: passes — The authors put it forward as true.
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- 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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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 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
plaindirect- Asserted: passes — The authors put it forward as true.
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- 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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
“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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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
“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
plaindirect- Asserted: passes — The authors put it forward as true.
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- 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
boosteddirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
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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
plain- Asserted: passes — The authors put it forward as true.
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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
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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
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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
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“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
hedged- Asserted: passes — The authors put it forward as true.
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“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
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
hedgedconditional- Asserted: passes — The authors put it forward as true.
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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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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
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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
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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
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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
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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
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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
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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
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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
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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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“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
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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
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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
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Claims other papers make about this one
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The cited source says what the claim attributes to it.
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
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
“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]
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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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > Experimental subjects and stereotactic surgery
“For all in vivo electrophysiology experiments, mice were implanted with a 16-wire (4 × 4 configuration, wire diameter∼30µm) tungsten multielectrode array (MEA)”
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > In vivo anesthetized electrophysiology
“Extracellular neural activity was recorded using a glass recording electrode (5 − 10 MΩ: and filled with 0.5 M NaCl).”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > Experimental subjects and stereotactic surgery
“For all in vivo electrophysiology experiments, male mice were unilaterally injected with 0.5 µl of purified and concentrated adeno-associated virus (AAV)”
§ Distinct extended amygdala circuits for divergent motivational states > Online methods > In vivo anesthetized electrophysiology
“C57BL/6J mice were bilaterally injected with 0.3 µl of AAV5-CaMKIIa-ChR2-eYFP into the BNSTv.”
Citations
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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…”
BackgroundMethodThe mesolimbic dopamine reward circuit in depression
Nestler, E. J., & Carlezon, W. A. (2006) · Biological Psychiatry · doi:10.1016/j.biopsych.2005.09.018 · Cited by 2,059 · cited 3×
“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…”
BackgroundMethodPhasic vs Sustained Fear in Rats and Humans: Role of the Extended Amygdala in Fear vs Anxiety
Davis, M., Walker, D. L., Miles, L., & Grillon, C. (2010) · Neuropsychopharmacology · doi:10.1038/npp.2009.109 · Cited by 1,513
Neuron-type-specific signals for reward and punishment in the ventral tegmental area
Cohen, J. Y., Haesler, S., Vong, L., Lowell, B. B., & Uchida, N. (2012) · Nature · doi:10.1038/nature10754 · Cited by 1,318
Input-specific control of reward and aversion in the ventral tegmental area
Lammel, S., Lim, B. K., Ran, C., Huang, K. W., Betley, M. J., Tye, K. M., Deisseroth, K., & Malenka, R. C. (2012) · Nature · doi:10.1038/nature11527 · Cited by 1,300
Leptin Action on GABAergic Neurons Prevents Obesity and Reduces Inhibitory Tone to POMC Neurons
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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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Sorted by citations
Items 401–500 of 703
Ni, R., Luo, P.-H., Shu, Y., Chen, J., & Zhou, J. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.07.017 · Cited by 19
Sampedro‐Piquero, P., Moreno‐Fernández, R. D., Begega, A., López, M., & Santín, L. J. (2022) · Addiction Biology · doi:10.1111/adb.13158 · Cited by 19
“For instance, studies have revealed persistent alcoholinduced neurobiological changes within the prefrontal cortex (PFC), the hippocampus and the amygdala integrally involved in governing diverse emotional states [12, 13, 14].”
BackgroundAn insular cortical circuit required for itch sensation and aversion
Zheng, J., Zhang, X. M., Tang, W., Li, Y., Wang, P., Jin, J., Luo, Z.-Y., Fang, S., Yang, S., Wei, Z., et al. (2024) · Current Biology · doi:10.1016/j.cub.2024.02.060 · Cited by 20
Update on Nonhuman Primate Models of Brain Disease and Related Research Tools
Qiao, N., Ma, L., Zhang, Y., & Wang, L. (2023) · Biomedicines · doi:10.3390/biomedicines11092516 · Cited by 18
“The ventral BNST regulates anxiety through its innervation of the VTA, with the activity of glutamatergic ventral BNST neurons projecting to the VTA producing anxiety-like behavior and ventral BNST gamma-aminobutyric neurons producing anti-anxiety effects through parallel pathways [102].”
Anxiety is the sum of its parts
Johansen, J. P. (2013) · Nature · doi:10.1038/nature12087 · Cited by 18
Deyama, S., Sugano, Y., Mori, S., Amano, T., Yoshioka, M., Kaneda, K., & Minami, M. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.03.008 · Cited by 18
Navabpour, S., Rezayof, A., & Ghasemzadeh, Z. (2021) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2021.174417 · Cited by 17
Identifying Parabrachial Neurons Selectively Regulating Satiety for Highly Palatable Food in Mice
Rodriguez, E., Ryu, D., Zhao, S., Han, B.-X., & Wang, F. (2019) · eNeuro · doi:10.1523/eneuro.0252-19.2019 · Cited by 19
“One week later, the animals were subjected to a two-chamber RTPP test in light cycle, using a modified method described in previous studies (Stamatakis and Stuber, 2012; Jennings et al., 2013).”
MethodZhao, J., Jia, H., Ma, P., Zhu, D. Y., & Fang, Y. (2025) · Pharmacological Research · doi:10.1016/j.phrs.2025.107717 · Cited by 20
Huijgens, P. T., Heijkoop, R., & Snoeren, E. M. S. (2021) · Behavioural Brain Research · doi:10.1016/j.bbr.2021.113206 · Cited by 17
Halladay, L. R., & Herron, S. M. (2022) · Neuropharmacology · doi:10.1016/j.neuropharm.2022.109404 · Cited by 19
A sex-specific role for the bed nucleus of the stria terminalis in proactive defensive behavior
Guerra, D. P., Wang, W., de Souza, K. A., & Moscarello, J. M. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-023-01581-9 · Cited by 20
Anterior cingulate cross-hemispheric inhibition via the claustrum resolves painful sensory conflict
Koga, K., Kobayashi, K., Tsuda, M., Pickering, A. E., & Furue, H. (2024) · Communications Biology · doi:10.1038/s42003-024-06008-9 · Cited by 17
Establishing connectivity through microdissections of midbrain stimulation-related neural circuits
Skandalakis, G. P., Neudorfer, C., Payne, C. A., Bond, E. S., Tavakkoli, A. D., Barrios‐Martinez, J., Trutti, A. C., Koutsarnakis, C., Coenen, V. A., Komaitis, S., et al. (2024) · Brain · doi:10.1093/brain/awae173 · Cited by 17
“112 The BNST has been used successfully as a DBS target for OCD and MDD. 9,113 This raises the question of whether therapeutic effects of BNST and VTA DBS for affective disorders are both facilitated through the pathway we identified.”
MethodTargeting the GABAB Receptor for the Treatment of Substance Use Disorder
Frankowska, M., Przegaliński, E., & Filip, M. (2016) · Springer eBooks · doi:10.1007/978-3-319-46044-4_14 · Cited by 18
Value, drug addiction and the brain
Loganathan, K., & Ho, E. T. W. (2021) · Addictive Behaviors · doi:10.1016/j.addbeh.2021.106816 · Cited by 18
Britt, J. P., McDevitt, R. A., & Reed, S. J. (2014) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s45896 · Cited by 17
“79 The behavioral and physiological components of anxiety can be dissociated via other BNST projections as well.”
Pina, M. M., & Cunningham, C. L. (2016) · Behavioural Brain Research · doi:10.1016/j.bbr.2016.06.063 · Cited by 16
“Doses were chosen based on previously published intracranial work in mice [9,21,22].”
MethodPedersen, W. S., Schaefer, S. M., Gresham, L. K., Lee, S. D., Kelly, M. P., Mumford, J. A., Oler, J. A., & Davidson, R. J. (2019) · NeuroImage · doi:10.1016/j.neuroimage.2019.116428 · Cited by 16
Cook-Snyder, D. R., Jones, A., & Reijmers, L. G. J. E. (2015) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2015.00056 · Cited by 16
“…the 1.3 kb Camk2a promoter to drive transgene expression in Camk2a-expressing projection neurons in various brain regions (Dittgen et al., 2004; Nathanson et al., 2009; Johansen et al., 2010; Lee et al., 2010; Stuber et al., 2011; Tye et al., 2011; Jennings et al., 2013; Nieh et al., 2015).”
BackgroundMethodResultInfluentialConditioned task-set competition: Neural mechanisms of emotional interference in depression
Stolicyn, A., Steele, J. D., & Seriès, P. (2016) · Cognitive Affective & Behavioral Neuroscience · doi:10.3758/s13415-016-0478-4 · Cited by 18
Jia, X., Chen, S.-P., Li, X., Tao, S., Lai, J., Liu, H., Huang, K., Tian, Y., Wei, P.-F., Yang, F., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111586 · Cited by 14
Daniel, S., Menigoz, A., Guo, J., Ryan, S. J., Seth, S., & Rainnie, D. G. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.03.013 · Cited by 16
Rossetti, I., Zambusi, L., Maccioni, P., Sau, R., Provini, L., Castelli, M. P., Gonciarz, K., Colombo, G., & Morara, S. (2019) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2019.00158 · Cited by 16
“…morphine; Vranjkovic et al., 2017), in increased drinking behavior associated with chronic alcohol exposure and withdrawal (as regulator of anxiety; Kash, 2012), and its intrinsic anxiogenic and anxiolytic circuits can be differentially modulated by specific drugs of abuse (e.g., cocaine, alcohol;…”
BackgroundMesencephalic dopamine neurons are essential for modafinil‐induced arousal
Yang, Y., Dong, H., Shen, Y., Li, L., Lazarus, M., Qu, W., & Huang, Z. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15660 · Cited by 19
“Dorsal raphé nucleus dopamine terminals are biased to the bed nucleus of the stria terminalis and the central nucleus of the amygdala, two regions known to bi-directionally affect motivated behaviour and regulate complex emotional states (Jennings et al., 2013).”
BackgroundRoss, R., Mandelblat-Cerf, Y., & Verstegen, A. M. J. (2016) · Harvard Review of Psychiatry · doi:10.1097/hrp.0000000000000111 · Cited by 15
Grecucci, A., Chiffi, D., Marzio, F. D., Job, R., & Frederickson, J. J. (2016) · InTech eBooks · doi:10.5772/65374 · Cited by 19
“Glutamatergic vBNST cells show an increase of activity during a foot‐shock session, while GABAergic cells are inhibited [70].”
BackgroundLinsambarth, S., Moraga‐Amaro, R., Quintana-Donoso, D., Rojas, S., & Stehberg, J. (2017) · InTech eBooks · doi:10.5772/intechopen.68618 · Cited by 17
“In yet another study, it was reported that the stimulation of VTA‐projecting BNST glutamatergic neurons has anxiogenic effects, while the activation of VTA‐projecting BNST GABAergic neurons has anxiolytic effects, similar to the effects of direct inhibition of VTA GABAergic neurons [228].”
BackgroundNeuronal circuits of fear memory and fear extinction
Wotjak, C. T., & Pape, H. (2013) · e-Neuroforum · doi:10.1007/s13295-013-0046-0 · Cited by 22
Litvin, Y., Turner, C. A., Ríos, M. B., Maras, P. M., Chaudhury, S., Baker, M. R., Blandino, P., Watson, S. J., Akil, H., & McEwen, B. S. (2016) · Hormones and Behavior · doi:10.1016/j.yhbeh.2016.09.009 · Cited by 15
“, 1998), a network that has been implicated in addiction, anxiety and aggression (Davis et al., 2010; Jennings et al., 2013; Calcagnoli et al., 2014b; Zorrilla et al., 2014).”
BackgroundVerma, D., Tasan, R. O., Sperk, G., & Pape, H. (2018) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2018.01.011 · Cited by 15
“In particular, the ventral sector of the anterior BNST (BNSTav) seems well positioned to control anxiety-like responses, given its projections via the paraventricular hypothalamic nucleus that regulate the HPA axis, and its axonal connections with the ventral tegmental area (VTA) (Gungor and Paré, 2016; Herman, Ostran…”
InfluentialWu, H., Tambuyzer, T., Nica, I. G., Deprez, M., van Kuyck, K., Aerts, J., Huffel, S. V., & Nuttin, B. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.1872-15.2016 · Cited by 15
“The identification of three seemingly inverse frequency band responses in the BNST during compulsion may complement recent studies (Jennings et al., 2013; Kim et al., 2013), showing multiple distinct neuronal groups, some activated while others inhibited, in the BNST during anxiety-like behavior.”
BackgroundResultSex Differences in the Social Behavior Network and Mesolimbic Dopamine System
Greenberg, G. D., & Trainor, B. C. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-802114-9.00004-4 · Cited by 16
“Both excitatory and inhibitory projections from the anterior ventral BNST to the VTA were identified using a combination of optogenetic stimulation and electrophysiology (Jennings et al., 2013).”
MethodFujita, A., Zhong, L., Antony, M. S., Chamiec-Case, E., Mickelsen, L. E., Kanoski, S. E., Flynn, W. F., & Jackson, A. C. (2021) · Journal of Neuroscience · doi:10.1523/jneurosci.2600-20.2021 · Cited by 15
Fudge, J. L., Kelly, E. A., & Hackett, T. A. (2022) · Journal of Neuroscience · doi:10.1523/jneurosci.1453-22.2022 · Cited by 14
“Furthermore, driving BSTLP VGluT2 versus VGAT neurons in male mice using optogenetic techniques is anxiogenic and anxiolytic, respectively, and associated with differential midbrain targets (Jennings et al., 2013).”
BackgroundIncreased subcortical brain activity in anxious but not depressed individuals
Hou, J., Liu, S., & van Wingen, G. A. (2023) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2023.02.013 · Cited by 15
Inan, S., Meissler, J. J., Shekarabi, A., Foss, J., Wiah, S., Eisenstein, T. K., & Rawls, S. M. (2022) · Brain Research · doi:10.1016/j.brainres.2023.148310 · Cited by 15
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Carboni, E., & Carta, A. R. (2022) · Journal of Integrative Neuroscience · doi:10.31083/j.jin2105144 · Cited by 16
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“The midbrain DA areas are also innervated by inputs from the extended amygdala that in turn receive cholinergic inputs [43,44], providing a pathway by which stressful events can regulate DA projections to the NAc [45].”
BackgroundInfluentialCadeddu, R., Jadzic, D., & Carboni, E. (2016) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2016.08.009 · Cited by 14
“, 2005), and possibly in the aetiology of depression (Jennings et al., 2013).”
BackgroundKaneko, T., Kaneda, K., Ohno, A., Takahashi, D., Hara, T., Amano, T., Ide, S., Yoshioka, M., & Minami, M. (2016) · European Journal of Neuroscience · doi:10.1111/ejn.13419 · Cited by 16
Research progress on the neural circuits mechanisms of anxiety
Gong, W. (2025) · Frontiers in Neural Circuits · doi:10.3389/fncir.2025.1609145 · Cited by 18
“Furthermore, BLA inputs to the adBNST and to vlBNST project to the ventral tegmental area (VTA), releasing multiple neurotransmitters that further influence anxiety regulation (Kim et al., 2013; Jennings et al., 2013).”
InfluentialA brain center that controls consummatory responses
Canovas, J. A., Wang, L., Mohamed, A. A. M., Abbott, L. F., & Zuker, C. S. (2025) · Cell · doi:10.1016/j.cell.2025.08.021 · Cited by 15
In vivo neurovascular response to focused photoactivation of Channelrhodopsin-2
Mester, J. R., Bazzigaluppi, P., Weisspapir, I., Dorr, A. E., Beckett, T. L., Koletar, M. M., Sled, J. G., & Stefanovic, B. (2019) · NeuroImage · doi:10.1016/j.neuroimage.2019.01.036 · Cited by 17
“We ultimately used power of the fibre-delivered stimulation typical of levels used in the literature (G.-Y. Wu et al., 2015; Jennings et al., 2013; Lammel et al., 2012; Iordanova et al., 2015; Anenberg et al., 2015) and optimized the focal stimulus power density to maximize response yield within appropriate power leve…”
Optogenetics: What it has uncovered in potential pathways of depression
Cheng, Z., Cui, R., Ge, T., Yang, W., & Li, B. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.104596 · Cited by 14
Polymorphic computation in locus coeruleus networks
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“, 2012), drug addiction (specifically stress-induced relapse) (Shaham et al., 2003; Dumont et al., 2005; Li et al., 2012; Jennings et al., 2013) and post-traumatic stress disorder (PTSD) (Hammack et al.”
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Glutamatergic Projection from the Ventral Tegmental Area to the Zona Incerta Regulates Fear Response
Wang, X.-Y., Zhang, H., Tong, K., Han, J. Y., Zhao, X.-Y., Song, Y., Hao, J., Sun, N., & Gao, C. (2024) · Neuroscience · doi:10.1016/j.neuroscience.2024.01.020 · Cited by 12
Energy state guides reward seeking via an extended amygdala to lateral hypothalamus pathway
Shrivastava, K., Athreya, V., Lu, Y., Luis-Islas, J., Han, A., Kowalski, T. F., & Rossi, M. A. (2025) · Nature Communications · doi:10.1038/s41467-025-59686-2 · Cited by 12
“Recent experiments have revealed that the LHA comprises functionally distinct cell types and with unique synaptic inputs 4,17 – 23 .”
Serotonergic modulation of the BNST–CeA pathway reveals sex differences in fear learning
Ravenelle, R., Lee, J., Fernandes-Henriques, C., Liu, J., Friedman, A. K., Likhtik, E., & Burghardt, N. S. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-02025-x · Cited by 13
“As the ventral BNST is implicated in recall of contextual fear conditioning by projections to the ventral tegmental area 44 , it is feasible that the additional involvement of serotonin in this region affected fear learning in males.”
Scheimann, J. R., Mahbod, P., Morano, R. L., Frantz, L., Packard, B. A., Campbell, K., & Herman, J. P. (2018) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2018.00325 · Cited by 12
“The CaMKII-Cre line used generally directs Cre expression in glutamatergic neurons (although CaMKII-Cre lines can direct GR deletion to non-glutamatergic cells in regions such as the striatum and bed nucleus of the stria terminalis; Klug et al., 2012; Jennings et al., 2013; Wang et al., 2013).”
MethodRanjan, V., Singh, S. P., Siddiqui, S. A., Tripathi, S., Khan, M. Y., & Prakash, A. (2017) · Psychiatry Investigation · doi:10.4306/pi.2017.14.3.350 · Cited by 14
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Serotonin and the neurobiology of anxious states
Lawther, A. J., Hale, M. W., & Lowry, C. A. (2020) · Handbook of behavioral neuroscience · doi:10.1016/b978-0-444-64125-0.00029-3 · Cited by 17
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Efficient and accurate extraction of in vivo calcium signals from microendoscopic video dataPreprint
Zhou, P., Resendez, S. L., Rodríguez-Romaguera, J., Jimenez, J., Neufeld, S. Q., Stuber, G. D., Hen, R., Kheirbek, M. A., Sabatini, B. L., Kass, R. E., et al. (2016) · arXiv (Cornell University) · doi:10.48550/arxiv.1605.07266 · Cited by 12
“urth row. (E) Temporal traces of all components in (C). Scalebars: 20 seconds. See S9 Video for demixing results. the stria terminalis (BNST) show strong responses to unpredictable footshock stimuli (Jennings et al. 2013). We therefore measured calcium dynamics in CaMKII-expressing neurons that were transfected with t…”
Self-citationHistamine signaling in the bed nucleus of the stria terminalis modulates stress-induced anxiety
Li, B., Chang, L., & Zhuang, Q. (2023) · Journal of Affective Disorders · doi:10.1016/j.jad.2023.05.035 · Cited by 11
Aversive Contexts Reduce Activity in the Ventral Subiculum- BNST Pathway
Urien, L., Cohen, S., Howard, S., Yakimov, A., Nordlicht, R., & Bauer, E. P. (2022) · Neuroscience · doi:10.1016/j.neuroscience.2022.06.019 · Cited by 10
Hattori, S., Hagihara, H., Ohira, K., Aoki, I., Saga, T., Suhara, T., Higuchi, M., & Miyakawa, T. (2013) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2013.00076 · Cited by 11
Smithers, H. E., Terry, J. R., Brown, J. T., & Randall, A. D. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00424 · Cited by 11
“More recently in vivo recordings from ventral BNST in awake male mice indicate that, although heterogeneous, firing rates in active cells that project to VTA average around 5 Hz, similar to the spontaneous firing level we see in slices (Jennings et al., 2013).”
A novel GPR55-mediated satiety signal in the oval Bed Nucleus of the Stria Terminalis
Hawken, E. R., Normandeau, C. P., Gregory, J. G., Cécyre, B., Bouchard, J., Mackie, K., & Dumont, É. C. (2019) · Neuropsychopharmacology · doi:10.1038/s41386-018-0309-0 · Cited by 11
Russell, J. S., Trouche, S. G., & Reijmers, L. G. J. E. (2020) · eNeuro · doi:10.1523/eneuro.0163-20.2020 · Cited by 11
“Serotonin from the DRN activates neurons in the BNST that evoke fear behavior through the local suppression of anxiolytic ventral BNST projections (Jennings et al., 2013; Marcinkiewcz et al., 2016), providing potential sites where the fear engram may be regulated.”
Kaouane, N., Ada, S., Hausleitner, M., & Haubensak, W. E. (2021) · Frontiers in Neural Circuits · doi:10.3389/fncir.2021.772512 · Cited by 12
Contestabile, A., Casarotto, G., Musardo, S., Espinosa, P., Maltese, F., Jiang, Y., Bellone, C., & Glangetas, C. (2023) · European Journal of Neuroscience · doi:10.1111/ejn.16043 · Cited by 8
“…innervations notably from the ventral subiculum, basolateral amygdala and insular cortex (Gehrlach et al., 2020; Luchsinger et al., 2021; Méndez-Ruette et al., 2019), regions which control anxiety (Glangetas et al., 2017; Jennings et al., 2013; Kim et al., 2013; Radley & Sawchenko, 2011).”
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Experience-dependent information routing through the basolateral amygdala shapes behavioral outcomes
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“14 For The NAcc and the bed nucleus of the stria terminalis (BnST), both receiving direct inputs from the BLA, 29,30 are strategically positioned as primary targets for downstream recruitment by the amygdala.”
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“More specifically, in vivo photostimulation of BNST-glutametergic projections to the VTA resulted in aversive and anxiogenic behavioral phenotypes, while activation of BNST-GABAergic projections produced rewarding and anxiolytic phenotypes.”
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“This area has received increased attention in light of recent physiological and functional studies (Daniel and Rainnie 2016; Deisseroth 2014; Jennings et al. 2013; Johansen 2013; Kim et al. 2013).”
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“Although recent research has shown anxiogenic and anxiolytic effects following the activation of different subregions in the anterior BNST (Jennings et al., 2013; Kim et al., 2013), little is known about how the posterior BNST (pBNST) contributes to emotional processing.”
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“In this regard an important finding is that optogenetic stimulation of specific VTA afferent pathways can produce aversion-related behaviors (Jennings et al., 2013; Lammel et al., 2012; Nieh et al., 2016; Stamatakis and Stuber, 2012).”
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“For example, protective mechanisms, such as BNST glutamate inputs to nondopaminergic neurons in the VTA that drive aversion and block reward (Jennings et al., 2013; Vranjkovic et al., 2017) may be recruited by Nic+EtOH exposure in adults to increase pVTA cFos expression and subsequently inhibit exploration in a novel…”
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“It is also of note that downstream of the BNSTV is the ventral tegmental area, which is important to an animal’s motivational state [45], and perturbation of this signaling pathway would alter an animal’s behavioral output.”
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“Multiple studies have indicated that the BNST send projections into the parabrachial nucleus, the lateral hypothalamus, the periaqueductal gray, the central nucleus of the amygdala, and the ventral tegmental area (Jennings et al., 2013).”
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“In contrast, the anxiety level was reduced when the inhibitory neurons in the BNST were stimulated (Jennings et al., 2013; Kim et al., 2013).”
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Self-citationAmygdalostriatal transition zone neurons encode sustained cue responses to guide defensive behaviors
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“Recently, Jennings et al. (2013) demonstrated that optogenetic stimulation of BNST GABAergic neurons projecting to the VTA elicits a rewarding and anxiolytic state.”
Background
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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