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Cited by 310Memory and Neural MechanismsNeuroscience and Neuropharmacology ResearchStress Responses and Cortisol

Control of Stress-Induced Persistent Anxiety by an Extra-Amygdala Septohypothalamic Circuit

Open access
Anthony, Todd E., Dee, Nick, Bernard, Amy, Lerchner, Walter, Heintz, Nathaniel, Anderson, David J.·2014·Cell
DOI 10.1016/j.cell.2013.12.040PMC PMC3982923
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Abstract

The extended amygdala has dominated research on the neural circuitry of fear and anxiety, but the septo-hippocampal axis plays an important role as well. The lateral septum (LS) is thought to suppress fear and anxiety, through its outputs to the hypothalamus. However, this structure has not yet been dissected using modern tools. The type 2 CRF receptor (Crfr2) marks a subset of LS neurons, whose functional connectivity we have investigated using optogenetics. Crfr2+ cells include GABAergic projection neurons that connect with the anterior hypothalamus. Surprisingly, we find that these LS outputs enhance stress-induced behavioral measures of anxiety. Furthermore, transient activation of Crfr2+ neurons promotes, while inhibition suppresses, persistent anxious behaviors. LS Crfr2+ outputs also positively regulate circulating corticosteroid levels. These data identify a subset of LS projection neurons that promote, rather than suppress, stress-induced behavioral and endocrinological dimensions of persistent anxiety states, and provide a cellular point-of-entry to LS circuitry.

AI snapshot

Written from the paper’s full text.

TL;DR

Crfr2α marks a subset of lateral septum GABAergic projection neurons that promote, rather than suppress, stress-induced persistent anxiety. Their anxiogenic effects are mediated at least partly by inhibitory projections to the anterior hypothalamus, with downstream di-synaptic influence on PVN function and corticosterone.

Key findings

  • Crfr2 is expressed mainly by LS GABAergic neurons: 1,765/2,076 (85.0%) Crfr2+ cells expressed Gad2, with no overlap with glutamatergic or cholinergic markers.
  • Optogenetic activation of LS Crfr2α+ neurons at 15 Hz increased anxiety in light-dark box, open field, novel object, and elevated plus maze without changing locomotor activity; 30 min transient stimulation produced anxiety that persisted throughout 35 min of testing, was absent at 7-day retest, and did not occur at 1 Hz.
  • Photoinhibition of Crfr2α+ neurons during immobilization stress or during testing produced anxiolytic effects, but inhibition during testing without prior IMS did not, suggesting activity is required for both induction and expression of the stress-induced anxious state.
  • LS Crfr2α+ neurons project to anterior hypothalamus (AHA); CRACM found picrotoxin-sensitive IPSCs in 6/9 AHA cells (average amplitude 71.3±5.3 pA, latency 5.0±0.4 ms), and terminal manipulation in AHA was anxiolytic/anxiogenic. Anterograde HSV tracing and retrobead recordings indicated di-synaptic connections to PVN, and optogenetic stimulation increased corticosterone while terminal inhibition reduced it.

Methods

  • Generated Crfr2α-eGFPCre BAC transgenic mice and used Cre-dependent AAVs to express ChR2-YFP, eNpHR, ArchT, or tdTomato in LS Crfr2α+ neurons; behavioral testing used light-dark box, open field, novel object, and elevated plus maze, with immobilization stress and corticosterone measurements.
  • Circuit mapping combined in situ hybridization/double fluorescence ISH, slice electrophysiology, ChR2-assisted circuit mapping, cholera toxin subunit B retrograde tracing, retrobeads, and Cre-dependent anterograde HSV129ΔTK-TT transneuronal tracing.
  • Main analyses compared optogenetic and control groups across behavioral assays, electrophysiological responses, and circulating corticosterone; detailed statistical methods and behavioral sample sizes are not stated in the provided text.

Limitations

  • The paper states that the Crfr2α-eGFPCre line drives detectable Cre in only a subset of Crfr2 mRNA+ cells, leaving open the relationship of Cre−, Crfr2+ cells to anxiety.
  • The authors state that their data do not exclude intra-septal actions of some LS Crfr2α+ neurons, that whether local and long-range synapses arise from the same or different neurons is unclear, and that whether the endocrinological effect explains persistent anxiety is unclear.
  • Evident from the text: behavioral sample sizes and detailed statistics are not reported in the provided text, and baseline corticosterone was elevated by handling/anesthesia, indicating HPA activation under testing conditions.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.cell.2013.12.040

Cites

67 of 67 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 41 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Direct optogenetic stimulation of Crfr2α+ neurons during behavioral testing increases anxiety.

    “Photostimulation during testing significantly increased anxiety levels in the ChR2 group in all three assays relative to light-stimulated control animals injected with Cre-dependent AAV encoding hrGFP (Fig. 3K).”
    • Also stated in: § Optogenetic activation of Crfr2α+ neurons is anxiogenic · plain
      “Thus, direct optogenetic stimulation of Crfr2α+ neurons during behavioral testing increases anxiety (Fig. 3N).”
    Quote in the paperSubstantial claim
  • Findingown data

    Photoinhibition of Crfr2α+ neurons produces significant anxiolytic effects in eNpHR-injected mice relative to hrGFP controls, regardless of whether inhibition is done during IMS or testing.

    “Photoinhibition of Crfr2α+ neurons produced significant anxiolytic effects in eNpHR-injected mice relative to hrGFP controls, regardless of whether inhibition was done during IMS or testing (Figs. 4L,K).”
    Quote in the paperSubstantial claim
  • Findingown data

    Many eGFPCre+ LS cells are surrounded by pericellular baskets containing UCN3, a CRFR2 peptide ligand.

    “Immunostaining revealed that many eGFPCre+ cells are surrounded by pericellular baskets containing UCN3, a CRFR2 peptide ligand (Figs. 2N,O)”
    Quote in the paperNot a substantial claim
  • Findingown data

    Crfr2 mRNA is expressed by a subset of lateral septum (LS) cells.

    “In situ hybridization (ISH) revealed that Crfr2 mRNA is expressed by a subset of LS cells (Figs. 2A–E).”
    Quote in the paperSubstantial claim
  • Findingown data

    Almost 80% (77.9%) of tdT+ cells contained detectable eGFPCre+ nuclei.

    “Almost 80% (77.9%) of tdT+ cells contained detectable eGFPCre+ nuclei (Figs. 2Q,R).”
    Quote in the paperSubstantial claim
  • May combine two claims. 16
  • Classified as probably not a substantial claim. 19

  • May combine two claims.

    Findingown data

    Photoinhibition of LS Crfr2α+ terminal fields in the AHA during behavioral testing following IMS produced significant anxiolytic effects without altering locomotor behavior.

    “Photoinhibition of LS Crfr2α+ terminal fields in the AHA during behavioral testing following IMS produced significant anxiolytic effects without altering locomotor behavior, and no significant differences were observed in the absence of 532nm light (Figs. 6B–E and S6N,O).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Postsynaptic responses in AHA occurred with a latency of 5.0±0.4 ms, consistent with monosynaptic connectivity.

    “Responses occurred with a latency of 5.0±0.4 ms, consistent with monosynaptic connectivity (Debanne et al., 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Debanne et al., 2008 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Baseline CORT was elevated in eYFP control mice.

    “Control experiments indicated that experimental handling, including anaesthetization, of animals elevates circulating CORT (data not shown), and baseline CORT was elevated in eYFP control mice, indicating that the HPA axis was activated under the testing conditions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In recordings of RB+ cells in the AHA from Crfr2α-eGFPCre mice co-injected with Cre-dependent ChR2-YFP in the LS and retrobeads in the PVN, 4/9 cells showed monosynaptic IPSCs in response to a 2 ms pulse of 473 nm light, with average amplitude 74.6±33.4 pA and average latency 5.5±0.1 ms, sufficient to inhibit firing.

    “Recordings of RB+ cells in the AHA identified 4/9 cells that showed monosynaptic IPSCs in response to a 2ms pulse of 473nm light (average amplitude = 74.6±33.4pA; average latency = 5.5±0.1 ms) and that were sufficient to inhibit firing (Fig. 7G).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Experimental handling, including anaesthetization, elevates circulating corticosterone (CORT) in mice.

    “Control experiments indicated that experimental handling, including anaesthetization, of animals elevates circulating CORT (data not shown), and baseline CORT was elevated in eYFP control mice, indicating that the HPA axis was activated under the testing conditions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The anxiolytic effects of photoinhibition were predominant during illumination, and therefore unlikely to be due to rebound firing following photoinhibition offset.

    “Comparisons of light ON vs. OFF periods indicated that the anxiolytic effects were predominant during illumination, and therefore unlikely to be due to rebound firing following photoinhibition offset (Fig. S4G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The Crfr2α-eGFPCre BAC transgene is highly specific for Crfr2+ neurons but may be expressed in only a subset of such cells.

    “This indicates that the BAC transgene is highly specific for Crfr2+ neurons, but may be expressed in a subset of such cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Ongoing activity of Crfr2α+ neurons is required for both the induction and persistence of a stress-induced anxious state.

    “These data suggest that ongoing activity of Crfr2α+ neurons is required for both the induction and persistence of a stress-induced anxious state (Fig. 4N).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Antidromic stimulation of LS cell bodies may contribute to the behavioral effects of optogenetic terminal activation, but cannot be exclusively responsible given that photoinhibition of terminals in this region using ArchT was anxiolytic.

    “Antidromic stimulation of LS cell bodies may contribute to the behavioral effects of optogenetic terminal activation, but cannot be exclusively responsible given that photoinhibition of terminals in this region using ArchT was anxiolytic (Fig. 6E).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S1 (asserted).

    Premisecitation

    A prevailing view is that the output of the lateral septum serves to dampen fear and anxiety.

    “The robust and dramatic ‘septal rage’ phenotype that results from certain electrolytic, physical, or chemical lesions of the septum (Spiegel et al., 1940; Brady and Nauta, 1953; Albert and Richmond, 1976) have led to a prevailing view that the output of the LS serves to dampen fear and anxiety (Sheehan et al., 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sheehan et al., 2004 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The midbrain periaqueductal gray (PAG) is a region known to regulate defensive behaviors relevant to anxiety.

    “a region known to regulate defensive behaviors relevant to anxiety (Bandler and Shipley, 1994; Almeida-Santos et al., 2013).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bandler and Shipley, 1994 source

      Not checked in the free run.

    • cites Almeida-Santos et al., 2013 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    ChR2-YFP was spatially correlated with Cre expression and restricted to the LS, with no ChR2-YFP+ cell bodies detected outside this region.

    “ChR2-YFP was spatially correlated with Cre expression and restricted to the LS, with no ChR2-YFP+ cell bodies detected outside of this region (Figs. 3B–E and data not shown).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A variety of stressors induce immediate early gene (IEG) expression in subsets of LS neurons.

    “A variety of stressors induce immediate early gene (IEG) expression in subsets of LS neurons (reviewed in (Sheehan et al., 2004)).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sheehan et al., 2004 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Yellow light produced outward currents that hyperpolarized eNpHR-YFP+ neurons without detectable rebound firing even after prolonged, repeated photoinhibition, and were sufficient to suppress current injection-induced firing.

    “Slice recordings confirmed that yellow light produced outward currents that hyperpolarized eNpHR-YFP+ neurons without detectable rebound firing even after prolonged, repeated photoinhibition (Figs. S4A–D), and that were sufficient to suppress current injection-induced firing (Figs. 4F–H).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S1 (asserted). May combine two claims.

    Interpretationreasoning

    If LS Crfr2α+ neurons inhibit GABAergic AHA targets that project to the PVN, then LS Crfr2+ neurons should exert a net positive-acting influence on PVN function via a presumptive di-synaptic disinhibitory connection.

    “If so, then LS Crfr2+ neurons should exert a net positive-acting influence on PVN function, via a presumptive di-synaptic disinhibitory connection.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The robust and dramatic 'septal rage' phenotype results from certain electrolytic, physical, or chemical lesions of the septum.

    “The robust and dramatic ‘septal rage’ phenotype that results from certain electrolytic, physical, or chemical lesions of the septum (Spiegel et al., 1940; Brady and Nauta, 1953; Albert and Richmond, 1976) have led to a prevailing view that the output of the LS serves to dampen fear and anxiety (Sheehan et al., 2004).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Spiegel et al., 1940 source

      Not checked in the free run.

    • cites Brady and Nauta, 1953

      Not checked in the free run.

    • cites Albert and Richmond, 1976

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Classical lesions of the septum, including medial and lateral subdivisions, resulted in the septal rage phenotype characterized by exaggerated defensive responses to non-threatening stimuli.

    “Classical lesions of the septum, including both its medial and lateral subdivisions, resulted in the dramatic ‘septal rage’ phenotype, characterized by exaggerated defensive responses to non-threatening stimuli (Spiegel et al., 1940; Brady and Nauta, 1953).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Spiegel et al., 1940 source

      Not checked in the free run.

    • cites Brady and Nauta, 1953

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Reversible inactivation of the LS yielded phenotypes similar to the septal rage phenotype.

    “Reversible inactivation of the LS yielded similar phenotypes (Albert and Richmond, 1976; Albert and Wong, 1978).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Albert and Richmond, 1976

      Not checked in the free run.

    • cites Albert and Wong, 1978

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The LS is cellularly heterogeneous.

    “It is also cellularly heterogeneous (Risold and Swanson, 1997a).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Risold and Swanson, 1997a

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    A crescent-shaped pattern of eNpHR-YFP protein was restricted to the LS and correlated closely with Cre+ cells.

    “A crescent-shaped pattern of eNpHR-YFP protein was observed that was restricted to LS and correlated closely with Cre+ cells (Figs. 4B–E and data not shown).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The severity of a stressful encounter influences the degree of its anxiogenic consequences.

    “The severity of a stressful encounter is thought to influence the degree of its anxiogenic consequences (Adamec et al., 2006).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Adamec et al., 2006 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    Injection of a Cre-dependent AAV into Crfr2α-eGFPCre LS yielded ArchT expression in a pattern that correlated with Cre and enabled photoinhibition of cell bodies and axons.

    “Injection of a Cre-dependent AAV (Fig. 6A) into Crfr2α-eGFPCre LS yielded ArchT expression in a pattern that correlated with Cre and enabled photoinhibition of cell bodies and axons (Figs. S6B–M).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Anxiogenic cell populations in the lateral septum were inferred to act by providing local inhibition on anxiolytic output.

    “Anxiogenic cell populations in the LS were, therefore, inferred to act by providing local inhibition on such anxiolytic output (Henry et al., 2006).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Henry et al., 2006 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The LS receives topographically organized inputs from the hippocampus and is reciprocally connected with the hypothalamus.

    “The LS receives topographically organized inputs from the hippocampus (Risold and Swanson, 1996) and is in turn reciprocally connected with the hypothalamus (Risold and Swanson, 1997b) (Fig. 1A).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Risold and Swanson, 1996

      Not checked in the free run.

    • cites Risold and Swanson, 1997b

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Crfr2 mutations increase anxiety, implying an anxiolytic function for the receptor.

    “Indeed, Crfr2 mutations increase anxiety, implying an anxiolytic function for the receptor (Bale and Vale, 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bale and Vale, 2004 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The paraventricular nucleus (PVN) is part of the hypothalamic-pituitary-adrenocortical (HPA) axis.

    “the paraventricular nucleus (PVN), which is part of the hypothalamic-pituitary-adrenocortical (HPA) axis (reviewed in (Ulrich-Lai and Herman, 2009))”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ulrich-Lai and Herman, 2009 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    LS injections of agonists of the type 2 corticotropin-releasing factor receptor (Crfr2) have resulted in increased anxiety.

    “For example, LS injections of agonists of the type 2 corticotropin-releasing factor receptor (Crfr2) have resulted in increased anxiety (Radulovic et al., 1999; Bakshi et al., 2002; Henry et al., 2006).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Radulovic et al., 1999 source

      Not checked in the free run.

    • cites Bakshi et al., 2002 source

      Not checked in the free run.

    • cites Henry et al., 2006 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    LS Crfr2α+ neurons inhibit GABAergic targets in the AHA that in turn project to the PVN, and these effects are mediated at least in part via inhibition of GABAergic targets within the AHA.

    “Our data suggest that LS Crfr2α+ neurons inhibit GABAergic targets in AHA that in turn project to PVN.”
    • Also stated in: § LS Crfr2α+ neurons act via inhibitory projections to the medial hypothalamus · hedged
      “These effects are mediated at least in part via the inhibition of GABAergic targets within the AHA (Figs. 7L and S7A–H).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Photostimulation of excitatory basolateral amygdala projections to the central amygdala resulted in an acute anxiolytic effect that rapidly dissipated upon cessation of stimulation.

    “For example, photostimulation of excitatory basolateral amygdala projections to central amygdala resulted in an acute anxiolytic effect that rapidly dissipated upon cessation of stimulation (Tye et al., 2011).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Tye et al., 2011 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Optogenetic stimulation of Drd1a+ neurons in the oval nucleus of the BNST acutely but reversibly elevated anxiety.

    “Similarly, optogenetic stimulation of Drd1a+ neurons in the oval nucleus of BNST acutely but reversibly elevated anxiety (Kim et al., 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kim et al., 2013 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    LS neurons in general send recurrent GABAergic collaterals that terminate on other neurons throughout the LS.

    “LS neurons in general are thought to send recurrent GABAergic collaterals that terminate on other neurons throughout the LS (Sheehan et al., 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sheehan et al., 2004 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The BNST contains distinct anxiogenic and anxiolytic GABAergic neuronal subsets with unique patterns of long-range connections.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Jennings et al., 2013 source

      Not checked in the free run.

    • cites Kim et al., 2013 source

      Not checked in the free run.

32 of 32

  • The paper relies on this without support.

    The lateral septum has not yet been dissected using modern tools.

    “However, this structure has not yet been dissected using modern tools.”

  • The paper relies on this without support.

    The light-dark box, open field, novel object, and elevated plus maze behavioral assays in mice measure anxiety states relevant to human anxiety.

    “Three behavioral tests of anxiety were used: light-dark box (LDB), open field (OF), and novel object (NO)(Figs. 3I,J)”

  • The paper relies on this without support.

    Optogenetic stimulation of Crfr2α+ neurons at 15 Hz mimics their natural activity during anxiety.

    “We therefore chose a photostimulation rate of 15 Hz, which is in the range of natural firing rates of LS neurons in anxiogenic environments.”

  • The paper relies on this without support.

    Anxiety states are persistent.

    “One feature of anxiety states is their persistence.”

  • The paper relies on this without support.

    The PVN regulates corticosterone release.

    “a structure that regulates CORT release”

  • The paper relies on this without support.

    Optogenetic manipulations of specific neuronal subpopulations that lead to changes in corticosterone levels have not previously been reported.

    “To our knowledge, optogenetic manipulations of specific neuronal subpopulations that lead to changes in corticosterone levels have not previously been reported.”

  • The paper relies on this without support.

    The lateral septum has not previously been subjected to functional dissection of its genetically defined constituent neuronal subpopulations.

    “The LS has long been implicated in the control of stress responses and anxiety, but has not previously been subjected to functional dissection of its genetically defined constituent neuronal subpopulations.”

  • The paper relies on this without support.

    The PVN positively regulates the HPA axis.

    “since the PVN positively regulates the HPA axis.”
8 of 8

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?

  • CRFR activation in the lateral septum increases anxiety-related phenotypes by way of activation of CRFR type 2-expressing GABAergic projection neurons residing there.

    “Corticotropin releasing factor receptor (CRFR) activation in the lateral septum increases anxiety-related phenotypes96 by way of activation of CRFR type 2–expressing GABAergic projection neurons residing there97.”

    From Resolving the neural circuits of anxiety (2015) · cites this paper as [97]

  • The resultant disinhibition of the paraventricular nucleus of the hypothalamus and periaqueductal gray promotes neuroendocrine and behavioral aspects of the persistent anxiety state.

    “The resultant disinhibition of these regions promotes neuroendocrine and behavioral aspects of the persistent anxiety state97, which redouble the complementary actions of CeA and BNST activation.”

    From Resolving the neural circuits of anxiety (2015) · cites this paper as [97]

  • Activation of CRFR type 2-expressing GABAergic projection neurons in the lateral septum results in inhibition of cells in the anterior hypothalamic area, which themselves inhibit the paraventricular nucleus of the hypothalamus and periaqueductal gray.

    “Activation of these neurons results in inhibition of cells in the anterior hypothalamic area, which themselves inhibit the paraventricular nucleus of the hypothalamus and periaqueductal gray.”

    From Resolving the neural circuits of anxiety (2015) · cites this paper as [97]

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. Lo, 2011, A Cre-dependent, anterograde transsynaptic viral tracer for mapping output pathways of genetically marked neurons, Neuron, 72, 938, 10.1016/j.neuron.2011.12.002 · DOI
  2. Madisen, 2010, A robust and high-throughput Cre reporting and characterization system for the whole mouse brain, Nat. Neurosci., 13, 133, 10.1038/nn.2467 · DOI · Paper page
  3. Mongeau, 2003, Neural correlates of competing fear behaviors evoked by an innately aversive stimulus, J. Neurosci., 23, 3855, 10.1523/jneurosci.23-09-03855.2003 · DOI

Cited by

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Related

Authors
Anthony, T. E., Dee, N., Bernard, A., Lerchner, W., Heintz, N., & Anderson, D. J.
Affiliations
  • California Institute of Technology (US)
  • Allen Institute for Brain Science (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
Anderson, David J.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2014-01
Volume
156
Issue
3
Pages
522-536
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2013.12.040
PMC
PMC3982923
OpenAlex
W2071358231
Semantic Scholar
b6c54fbdfd05ec69ecfb82a1b25aee27b37e7e40
Cited by
310
References
67
Citations by year
2026: 27 · 2025: 25 · 2024: 33 · 2023: 12 · 2022: 36 · 2021: 19 · 2020: 35 · 2019: 24 · 2018: 28 · 2017: 20 · 2016: 19 · 2015: 17 · 2014: 15
FWCI
13.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institutes of Health (1f32hd055198-01)
  • National Institute of Mental Health (R01MH085082, R01MH070053)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32 HD055198, 1F32HD055198-01)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
persistent anxiety, stress, lateral septum, anterior hypothalamus, corticotropin-releasing factor, GABAergic projection neurons, corticosteroids, optogenetic manipulation
MeSH terms
Adrenal Cortex Hormones, Amygdala, Animals, Anxiety, Behavior, Animal, Female, Hypothalamus, Male, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Stress, Physiological, Receptors, Corticotropin-Releasing Hormone, Septum of Brain, Mice

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