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• W2921744971 abstract "•Social fear conditioning induces robust and specific social fear in mice•The dmPFC participates in social fear expression•SST INs disinhibit principal neurons via their inhibition of FS-PV INs•The disinhibitory microcircuitry is crucial for social fear expression Fear behavior is under tight control of the prefrontal cortex, but the underlying microcircuit mechanism remains elusive. In particular, it is unclear how distinct subtypes of inhibitory interneurons (INs) within prefrontal cortex interact and contribute to fear expression. We employed a social fear conditioning paradigm and induced robust social fear in mice. We found that social fear is characterized by activation of dorsal medial prefrontal cortex (dmPFC) and is largely diminished by dmPFC inactivation. With a combination of in vivo electrophysiological recordings and fiber photometry together with cell-type-specific pharmacogenetics, we further demonstrated that somatostatin (SST) INs suppressed parvalbumin (PV) INs and disinhibited pyramidal cells and consequently enhanced dmPFC output to mediate social fear responses. These results reveal a previously unknown disinhibitory microcircuit in prefrontal cortex through interactions between IN subtypes and suggest that SST INs-mediated disinhibition represents an important circuit mechanism in gating social fear behavior. Fear behavior is under tight control of the prefrontal cortex, but the underlying microcircuit mechanism remains elusive. In particular, it is unclear how distinct subtypes of inhibitory interneurons (INs) within prefrontal cortex interact and contribute to fear expression. We employed a social fear conditioning paradigm and induced robust social fear in mice. We found that social fear is characterized by activation of dorsal medial prefrontal cortex (dmPFC) and is largely diminished by dmPFC inactivation. With a combination of in vivo electrophysiological recordings and fiber photometry together with cell-type-specific pharmacogenetics, we further demonstrated that somatostatin (SST) INs suppressed parvalbumin (PV) INs and disinhibited pyramidal cells and consequently enhanced dmPFC output to mediate social fear responses. These results reveal a previously unknown disinhibitory microcircuit in prefrontal cortex through interactions between IN subtypes and suggest that SST INs-mediated disinhibition represents an important circuit mechanism in gating social fear behavior. Fear is typically an adaptive feeling to an imminent threat and is helpful for animals and humans to avoid danger. Inappropriate fear, on the other hand, is a maladaptive response to environmental stimuli and is commonly observed in a number of psychiatric disorders including posttraumatic stress disorder (PTSD) and anxiety disorders (Buff et al., 2016Buff C. Brinkmann L. Neumeister P. Feldker K. Heitmann C. Gathmann B. Andor T. Straube T. Specifically altered brain responses to threat in generalized anxiety disorder relative to social anxiety disorder and panic disorder.Neuroimage Clin. 2016; 12: 698-706Crossref PubMed Scopus (42) Google Scholar, Nees et al., 2018Nees F. Witt S.H. Flor H. Neurogenetic Approaches to Stress and Fear in Humans as Pathophysiological Mechanisms for Posttraumatic Stress Disorder.Biol. Psychiatry. 2018; 83: 810-820Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, Sheynin et al., 2017Sheynin J. Shind C. Radell M. Ebanks-Williams Y. Gilbertson M.W. Beck K.D. Myers C.E. Greater avoidance behavior in individuals with posttraumatic stress disorder symptoms.Stress. 2017; 20: 285-293Crossref PubMed Scopus (26) Google Scholar). Social fear is one such inappropriate fear and represents a core behavioral symptom of social anxiety disorder (SAD), which is prevalent worldwide and causes disabling effects (American Psychiatric Association, 2013American Psychiatric AssociationDiagnostic and Statistical Manual of Mental Disorders (DSM-5). American Psychiatric Pub, 2013Crossref Google Scholar). The pathological mechanism for SAD is poorly understood and there are no satisfactory therapeutic options available (Stein and Stein, 2008Stein M.B. Stein D.J. Social anxiety disorder.Lancet. 2008; 371: 1115-1125Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar). It has been well established that the amygdala plays a determinant role in the control of fear and anxiety (Phelps and LeDoux, 2005Phelps E.A. LeDoux J.E. Contributions of the amygdala to emotion processing: from animal models to human behavior.Neuron. 2005; 48: 175-187Abstract Full Text Full Text PDF PubMed Scopus (2257) Google Scholar). At the same time, the amygdala is under functional regulation of various cortical and subcortical inputs. Recent evidence from both human and animal studies have implicated the prefrontal cortex (PFC) in the processes of fear regulation (Burgos-Robles et al., 2009Burgos-Robles A. Vidal-Gonzalez I. Quirk G.J. Sustained conditioned responses in prelimbic prefrontal neurons are correlated with fear expression and extinction failure.J. Neurosci. 2009; 29: 8474-8482Crossref PubMed Scopus (366) Google Scholar, Etkin et al., 2011Etkin A. Egner T. Kalisch R. Emotional processing in anterior cingulate and medial prefrontal cortex.Trends Cogn. Sci. 2011; 15: 85-93Abstract Full Text Full Text PDF PubMed Scopus (1995) Google Scholar, Karalis et al., 2016Karalis N. Dejean C. Chaudun F. Khoder S. Rozeske R.R. Wurtz H. Bagur S. Benchenane K. Sirota A. Courtin J. Herry C. 4-Hz oscillations synchronize prefrontal-amygdala circuits during fear behavior.Nat. Neurosci. 2016; 19: 605-612Crossref PubMed Scopus (190) Google Scholar). In particular, PFC hyperactivity is tightly linked to excessive and long-lasting fear states in patients with SAD (Buff et al., 2016Buff C. Brinkmann L. Neumeister P. Feldker K. Heitmann C. Gathmann B. Andor T. Straube T. Specifically altered brain responses to threat in generalized anxiety disorder relative to social anxiety disorder and panic disorder.Neuroimage Clin. 2016; 12: 698-706Crossref PubMed Scopus (42) Google Scholar, Kawashima et al., 2016Kawashima C. Tanaka Y. Inoue A. Nakanishi M. Okamoto K. Maruyama Y. Oshita H. Ishitobi Y. Aizawa S. Masuda K. et al.Hyperfunction of left lateral prefrontal cortex and automatic thoughts in social anxiety disorder: A near-infrared spectroscopy study.J. Affect. Disord. 2016; 206: 256-260Crossref PubMed Scopus (14) Google Scholar). To date, however, the neuronal substrates and local microcircuits underlying PFC network excitability and hence social fear expression are still elusive. Normal brain functions rely on a delicate balance between excitation and inhibition. To perform its complex operations, the mammalian cerebral cortex has evolved a large diversity of GABAergic interneurons (INs) based on differences in neuronal morphologies, electrophysiological properties, and neurochemical markers (Ascoli et al., 2008Ascoli G.A. Alonso-Nanclares L. Anderson S.A. Barrionuevo G. Benavides-Piccione R. Burkhalter A. Buzsáki G. Cauli B. Defelipe J. Fairén A. et al.Petilla Interneuron Nomenclature GroupPetilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex.Nat. Rev. Neurosci. 2008; 9: 557-568Crossref PubMed Scopus (1049) Google Scholar, Fishell and Rudy, 2011Fishell G. Rudy B. Mechanisms of inhibition within the telencephalon: “where the wild things are”.Annu. Rev. Neurosci. 2011; 34: 535-567Crossref PubMed Scopus (170) Google Scholar, Rudy et al., 2011Rudy B. Fishell G. Lee S. Hjerling-Leffler J. Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons.Dev. Neurobiol. 2011; 71: 45-61Crossref PubMed Scopus (837) Google Scholar, Somogyi and Klausberger, 2005Somogyi P. Klausberger T. Defined types of cortical interneurone structure space and spike timing in the hippocampus.J. Physiol. 2005; 562: 9-26Crossref PubMed Scopus (705) Google Scholar). Different subtypes of inhibitory INs could effectively control cortical network activity via feedforward, feedback inhibition, and/or disinhibitory mechanisms (Isaacson and Scanziani, 2011Isaacson J.S. Scanziani M. How inhibition shapes cortical activity.Neuron. 2011; 72: 231-243Abstract Full Text Full Text PDF PubMed Scopus (979) Google Scholar, Tremblay et al., 2016Tremblay R. Lee S. Rudy B. GABAergic Interneurons in the Neocortex: From Cellular Properties to Circuits.Neuron. 2016; 91: 260-292Abstract Full Text Full Text PDF PubMed Scopus (851) Google Scholar, Xu et al., 2013Xu H. Jeong H.Y. Tremblay R. Rudy B. Neocortical somatostatin-expressing GABAergic interneurons disinhibit the thalamorecipient layer 4.Neuron. 2013; 77: 155-167Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar). Moreover, recent evidence demonstrates functional correlates between specific cortical IN subtypes and distinct behaviors in sensory perception, motor integration, space coding, as well as working memory, attention, and reward processing (Kamigaki and Dan, 2017Kamigaki T. Dan Y. Delay activity of specific prefrontal interneuron subtypes modulates memory-guided behavior.Nat. Neurosci. 2017; 20: 854-863Crossref PubMed Scopus (116) Google Scholar, Kim et al., 2016aKim D. Jeong H. Lee J. Ghim J.W. Her E.S. Lee S.H. Jung M.W. Distinct Roles of Parvalbumin- and Somatostatin-Expressing Interneurons in Working Memory.Neuron. 2016; 92: 902-915Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, Kim et al., 2016bKim H. Ährlund-Richter S. Wang X. Deisseroth K. Carlén M. Prefrontal Parvalbumin Neurons in Control of Attention.Cell. 2016; 164: 208-218Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, Kvitsiani et al., 2013Kvitsiani D. Ranade S. Hangya B. Taniguchi H. Huang J.Z. Kepecs A. Distinct behavioural and network correlates of two interneuron types in prefrontal cortex.Nature. 2013; 498: 363-366Crossref PubMed Scopus (292) Google Scholar, Lee et al., 2012Lee S.H. Kwan A.C. Zhang S. Phoumthipphavong V. Flannery J.G. Masmanidis S.C. Taniguchi H. Huang Z.J. Zhang F. Boyden E.S. et al.Activation of specific interneurons improves V1 feature selectivity and visual perception.Nature. 2012; 488: 379-383Crossref PubMed Scopus (395) Google Scholar, Lee et al., 2013Lee S. Kruglikov I. Huang Z.J. Fishell G. Rudy B. A disinhibitory circuit mediates motor integration in the somatosensory cortex.Nat. Neurosci. 2013; 16: 1662-1670Crossref PubMed Scopus (448) Google Scholar, Miao et al., 2017Miao C. Cao Q. Moser M.B. Moser E.I. Parvalbumin and Somatostatin Interneurons Control Different Space-Coding Networks in the Medial Entorhinal Cortex.Cell. 2017; 171: 507-521.e17Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). In contrast, we know much less about the differential participation of cortical inhibitory IN subtypes in the control of emotional behaviors. In particular, it is unclear how distinct subtypes of inhibitory INs within PFC interact and hence contribute to social fear responses. Answers to these questions will not only reveal how PFC contributes to fear behaviors, but will also shed light on what circuit disturbances could cause social dysfunctions. To induce social fear in mice, we employed a social fear conditioning (SFC) paradigm (Menon et al., 2018Menon R. Grund T. Zoicas I. Althammer F. Fiedler D. Biermeier V. Bosch O.J. Hiraoka Y. Nishimori K. Eliava M. et al.Oxytocin Signaling in the Lateral Septum Prevents Social Fear during Lactation.Curr. Biol. 2018; 28: 1066-1078.e6Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar, Toth et al., 2012Toth I. Neumann I.D. Slattery D.A. Social fear conditioning: a novel and specific animal model to study social anxiety disorder.Neuropsychopharmacology. 2012; 37: 1433-1443Crossref PubMed Scopus (61) Google Scholar). In brief, a freely moving experimental mouse and a confined stimulus mouse were placed in a conditioning box. After a 2 min exploration, the experimental mouse was then given an electric foot shock each time as it investigated the stimulus mouse during a period of 20 min (Figure 1A; Video S1). Conditioned mice developed robust escape and avoidance behavior when oriented toward a conspecific, indicating successful acquisition of social fear following SFC (Video S2). To quantify social fear behavior, we used a three-chamber social interaction test, which is a widely used assay to examine social behavior in rodents (Figure 1B) (Moy et al., 2004Moy S.S. Nadler J.J. Perez A. Barbaro R.P. Johns J.M. Magnuson T.R. Piven J. Crawley J.N. Sociability and preference for social novelty in five inbred strains: an approach to assess autistic-like behavior in mice.Genes Brain Behav. 2004; 3: 287-302Crossref PubMed Scopus (959) Google Scholar). As compared to unconditioned control mice, those experienced SFC exhibited a dramatic decrease in the time spent in the social chamber (control: 315.3 ± 12.4 s, n = 9; conditioned: 100.1 ± 25.8 s, n = 9; p < 0.0001), the social interaction index (the difference in the time spent in the social and neutral chambers divided by the total time spent in both chambers) (control: 0.34 ± 0.04, n = 9; conditioned: −0.48 ± 0.12, n = 9; p < 0.0001), and times of social approaches (control: 20.1 ± 1.6, n = 9; conditioned: 8.7 ± 1.9, n = 9; p < 0.001) (Figures 1C–1E). The social fear behavior was further confirmed with a social preference-avoidance test (Figure 1H). Again, the conditioned mice spent significantly less time with stimulus mouse relative to unconditioned controls (control: 328.5 ± 27.6 s, n = 8; conditioned: 36.1 ± 14.0 s, n = 8; p < 0.0001) with a smaller social interaction index (the time spent in the social zone divided by the time spent in corners) (control: 9.75 ± 2.16, n = 8; conditioned: 0.22 ± 0.10, n = 8; p < 0.001) and less approach times (control: 34.5 ± 2.3, n = 8; conditioned: 11.4 ± 3.4, n = 8; p < 0.0001) (Figures 1I–1K). In addition to the striking reduction in social investigation, conditioned mice approached the stimulus mouse at a slow speed in stretched postures, behavioral indicators of an elevated fear state in rodents, which was not observed in unconditioned control mice (Figures 1F, 1G, 1L, and 1M) (Toth et al., 2012Toth I. Neumann I.D. Slattery D.A. Social fear conditioning: a novel and specific animal model to study social anxiety disorder.Neuropsychopharmacology. 2012; 37: 1433-1443Crossref PubMed Scopus (61) Google Scholar). It is worth noting that the male stimulus mice used in either test were different from the ones used during SFC. And indeed, when stimulus mouse was replaced with a female mouse, the social fear behavior was equally present as well (Figures S1A and S1B). Moreover, conditioned mice also avoided a non-aggressive female mouse that was introduced into their home cage (Figures S1C–S1F). These results indicate that conditioned mice developed fear not only to the particular stimulus mouse associated with conditioning but also to their conspecifics in general even in a natural social setting. In contrast, the conditioned mice did not exhibit fear responses to a novel object (Figures S1G and S1H), suggesting the specificity of fear to social stimulus. Besides, the conditioned mice were not accompanied by changes in locomotion, general anxiety, or depressive-like behaviors (Figure S2). Together, the SFC that we used could induce robust and specific social fear in mice without confounding behavioral alterations and thus represents a suitable animal paradigm to study the neural foundations underlying social fear. eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiJkM2NkYzg2ZTJkN2M2MDk5NGFiN2E5N2UwNmEzYjFmOSIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc3Njg4NzYzfQ.OtFOMPiX1v9PkfoolPkBzvZ3YTicRtiANsa5OsTysUrEoLFRX9TQpVS2KSkUm4UGxlyvKMtHasPfLlA98CzFLB7vvpTJua_mH5LWUtmaFxLPBP1ykrNpk5-o5YtfRVOf3rLxdWSN0Mrn1xeq0UWwADg--KKH5rEJ6si6-PxbyhRTMygvXM8FpOt9b4hRB_IcRRnoSF4vFZfszOdYLiIanpeV9lQCjeoiMIejqjZBIiXAPIFfIhsq8K63SQHLScogLQIZBpqp0Sf7xCJcp71n2dew3DAkHTHbzf0XGMNd02gU2bM6I6-SZkpWVBoDfUk6zA9-OxPsjVx96H-Nqw2knw Download .mp4 (2.02 MB) Help with .mp4 files Video S1. SFC, Related to Figure 1 eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiI0MGRmODk4MTIwNWFiY2ViZmQwNmMwZTgyYjMzN2JmOSIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc3Njg4NzYzfQ.InrmcHveR1o7vciBxlWn4fOp-ByWleSLAR2BpKMT17-vCqQJmDN2HboSBkbj1pV-OhVAzcDRpsJn5Y8ln4P7WUc75G_svyDBJ8uuHdB9jwaENznwDtghGeJ-uPFtWyM1l7nzuGaN-6w4Q_WwTsFUngn1-PTzLYl7UQRJJFppBFX_iSyhGyl2mn1kAFQrGyUY_6yjcQ6cRvJ-4TbMwC7sXI-wmCtx8ryZW0v-qgHxz4DU69uXVqFy0OkTL9YZG6PjPycaTYGZMdQunXfLyuJ0iydWwGd0b3zr5FtE3wFT6aR0OpcoqOJbutNC8rIEGt59j59oDNeRWNnd2g8NuEpMQA Download .mp4 (0.6 MB) Help with .mp4 files Video S2. Social Fear Responses of Conditioned Mouse in an Open Field, Related to Figure 1 Human imaging studies demonstrate that patients with SAD show abnormal hyperactivity in PFC (Buff et al., 2016Buff C. Brinkmann L. Neumeister P. Feldker K. Heitmann C. Gathmann B. Andor T. Straube T. Specifically altered brain responses to threat in generalized anxiety disorder relative to social anxiety disorder and panic disorder.Neuroimage Clin. 2016; 12: 698-706Crossref PubMed Scopus (42) Google Scholar, Kawashima et al., 2016Kawashima C. Tanaka Y. Inoue A. Nakanishi M. Okamoto K. Maruyama Y. Oshita H. Ishitobi Y. Aizawa S. Masuda K. et al.Hyperfunction of left lateral prefrontal cortex and automatic thoughts in social anxiety disorder: A near-infrared spectroscopy study.J. Affect. Disord. 2016; 206: 256-260Crossref PubMed Scopus (14) Google Scholar), we therefore next examined PFC neuronal reactions following social fear in conditioned mice. After exposure to a conspecific, a significant increase in the number of c-Fos positive cells was observed in dorsal medial PFC (dmPFC), including the prelimbic subregion (PrL) in mice with conditioned social fear (Figures 2A and 2B ). To determine whether dmPFC activity indeed contributed to social fear expression in conditioned mice, we employed a pharmacological approach with GABAa receptor agonist muscimol (MUS, 0.25 nmol, 150 nL/side) to rapidly inactivate dmPFC neurons in behaving mice (Figure 2C). Three-chamber social interaction test was used to evaluate the effect of dmPFC inactivation on social fear (Figure 2D). When compared with vehicle-treated controls (PBS), mice with MUS injection displayed a significant increase in time spent in the social chamber (PBS: 100.7 ± 25.9 s, n = 8; MUS: 247.1 ± 23.5 s, n = 8; p < 0.001), the social interaction index (PBS: −0.53 ± 0.10 s, n = 8; MUS: 0.06 ± 0.10 s, n = 8; p < 0.01), and times of social approaches (PBS: 7.8 ± 1.7, n = 8; MUS: 14.6 ± 1.5, n = 8; p < 0.01) (Figures 2E–2G). In addition, MUS-injected mice also exhibited significantly less stretched postures (PBS: 10.1 ± 1.5, n = 8; MUS: 1.5 ± 1.0, n = 8; p < 0.001) and increased approach speed (PBS: 5.6 ± 0.6 cm/s, n = 8; MUS: 10.5 ± 0.5 cm/s, n = 8; p < 0.0001), indicating a direct reduction of fear (Figures 2H and 2I). In comparison, dmPFC inactivation did not change the time spent in the social chamber in unconditioned control mice, suggesting that this manipulation neither nonspecifically increased social preference nor interfered with animals’ ability to differentiate between regions of their environment (the social versus neutral chambers) (Figures S3A–S3B). This finding is consistent with previous pharmacological inactivation study conducted in rats (Lungwitz et al., 2014Lungwitz E.A. Stuber G.D. Johnson P.L. Dietrich A.D. Schartz N. Hanrahan B. Shekhar A. Truitt W.A. The role of the medial prefrontal cortex in regulating social familiarity-induced anxiolysis.Neuropsychopharmacology. 2014; 39: 1009-1019Crossref PubMed Scopus (23) Google Scholar). Together, these results indicated that dmPFC plays an essential role in the expression of social fear behavior. In comparison, consistent with the patterns of c-Fos expression, MUS injection into the IL subregion failed to inhibit social fear, suggesting that IL is not involved in social fear expression (Figures 2J–2P). We also examined the role of dmPFC in social fear that was elicited by another commonly used paradigm, that is, social defeat (Franklin et al., 2017Franklin T.B. Silva B.A. Perova Z. Marrone L. Masferrer M.E. Zhan Y. Kaplan A. Greetham L. Verrechia V. Halman A. et al.Prefrontal cortical control of a brainstem social behavior circuit.Nat. Neurosci. 2017; 20: 260-270Crossref PubMed Scopus (105) Google Scholar). After 3 consecutive days of social defeat by CD1 mice, the experimental C57 mice developed social fear behaviors (Figures S4A–S4D). To test whether the social fear induced by social defeat is dependent on dmPFC, we inactivated dmPFC neurons with MUS (0.25 nmol, 150 nL/side). When compared with vehicle-treated controls (PBS), mice with MUS injection spent significantly more time with stimulus mouse in a social preference-avoidance test (Figures S4E–S4H). This result indicated that social fear induced in a more naturalistic way by social defeat is also dependent on dmPFC. In addition to dmPFC, c-Fos expression was markedly increased in the basolateral amygdala (BLA), and pharmacological inactivation of BLA largely reduced social fear responses (Figure S5). This finding is consistent with the well-established notion that BLA is required for the expression of conditioned fear (Phelps and LeDoux, 2005Phelps E.A. LeDoux J.E. Contributions of the amygdala to emotion processing: from animal models to human behavior.Neuron. 2005; 48: 175-187Abstract Full Text Full Text PDF PubMed Scopus (2257) Google Scholar). Indeed, the BLA inactivation led to a larger suppression of fear behavior than dmPFC inactivation did. Given the complexity of neuronal circuits underlying fear (Gross and Canteras, 2012Gross C.T. Canteras N.S. The many paths to fear.Nat. Rev. Neurosci. 2012; 13: 651-658Crossref PubMed Scopus (365) Google Scholar, Herry and Johansen, 2014Herry C. Johansen J.P. Encoding of fear learning and memory in distributed neuronal circuits.Nat. Neurosci. 2014; 17: 1644-1654Crossref PubMed Scopus (281) Google Scholar), it is likely that projections from brain regions other than dmPFC to BLA also participate in social fear modulation. The dmPFC is a complex circuitry composed of glutamatergic excitatory neurons and GABAergic inhibitory INs. To further explore the dmPFC microcircuitry underlying social fear, we employed chronic electrophysiological recordings (Figure 3A). The well-isolated neurons (241 from 19 conditioned mice; 133 from 8 unconditioned mice) were categorized into narrow-spiking (NS; n = 68, trough to peak duration 239.62 ± 6.57 μs) putative inhibitory INs and wide-spiking (WS; n = 306, trough to peak duration 474.50 ± 2.78 μs) putative pyramidal neurons according to spike features (Figures S6A–S6C) (Kim et al., 2016aKim D. Jeong H. Lee J. Ghim J.W. Her E.S. Lee S.H. Jung M.W. Distinct Roles of Parvalbumin- and Somatostatin-Expressing Interneurons in Working Memory.Neuron. 2016; 92: 902-915Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, Kim et al., 2016bKim H. Ährlund-Richter S. Wang X. Deisseroth K. Carlén M. Prefrontal Parvalbumin Neurons in Control of Attention.Cell. 2016; 164: 208-218Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar). The putative inhibitory INs were further classified into fast-spiking parvalbumin (FS-PV) INs (average firing rate >10 Hz) and non-FS NS neurons based on neuronal firing rate (Figure 3B) (Kim et al., 2016bKim H. Ährlund-Richter S. Wang X. Deisseroth K. Carlén M. Prefrontal Parvalbumin Neurons in Control of Attention.Cell. 2016; 164: 208-218Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar). In a separate cohort of animals, we also used optogenetic tagging method to identify FS-PV INs (Figures S6D–S6G). A total of 19 opto-tagged dmPFC FS-PV INs (10 from 5 conditioned mice; 9 from 5 unconditioned mice) was recorded (Figures 3B, 3F, and 3J). We then measured the spiking activity of dmPFC neurons during social fear expression, that is, when a conditioned mouse was confronted with a confined stimulus mouse in a social approach test (Figure 3A). During the test, the experimental mice exhibited occasional risk assessment behaviors. In specific, the experimental mice slowly approached the stimulus mouse in a stretched posture and then quickly retreated from the stimulus mouse, indicating an elevated fear state (Figures 1F, 1G, 1L, and 1M; Videos S3 and S4). We therefore focused on the neuronal activities during such risk assessment, the period when experimental mouse was approaching and orientating at the stimulus mouse (Figures 3C and 3E). eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiI0Mjc3N2M5ZjQ3NjJkNmQ4NWZmMTVmZDMxNDA5OTIxYiIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc3Njg4NzYzfQ.DfBF0noSc1vEORPxdFAPx5wWCa8HJlARdPBfyTZXCUPZpmY8Pg7khmvUM6Wq6RtE7KwnRC2EVlB2bKe5EzHXuSGIrUvJZ2PnbV4XS4h1NcVHkiBMshIm8LAFrBacCyAXedVlldarGcMvyG31AmsavPSg1gjJojhsi_KF4CCFTSH1Sf3b13tSGcyXLxpJDm1AKBgIKKwWglN_W5wRVpaM2vznXWlupmodaLXHCcw2XWj2Jhr8d1dP9sAV5pGzubuOfhtdHJws8DmGotHQo-IUanoihKfZFdLZSEAXtk1_7LcRVpilm5Qmh7xPsFh5Ij85AMRlyLgcAJHV4sjlJEiaZw Download .mp4 (1.41 MB) Help with .mp4 files Video S3. Pyramidal Firing Increases upon Social Fear Expression, Related to Figure 3 eyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiJjYjgyNGYxYWFjZTE5MGQ5NzhjMGQ3MDIxZDk0NWMyMCIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc3Njg4NzYzfQ.TvAelxhy8nUTbblg2L2-jJJqC20VlMmKHW9O8s_Q5JTG2zVqfZD3-KLLsFEn1WBYP3Q8-baW6KF_9sP6cHGrW3veuEqymmQ-M4QCZHIlRDabPzFnb9kILtedalVIvB3E0E9umBsxeYCrTJdLt48yJpGy0BLH9JtEP6HJ92b_TYXTJsgozlyJd6XM6RQXbwWxTKjzrw4dquBXy66NyHbisl5PTEwK1gKu6h7lFeu72_Rh4aInSvdQYNLsB2KuW-aVFS_ACEQhWS_oWOMfKtEV4xZN9eOlpjL4LzkxSLZl1xfqpUAB0OJdHnIhBLm13mHQ_A-LAQuaQLOyB_Yn3VOOSg Download .mp4 (3.08 MB) Help with .mp4 files Video S4. FS-PV Firing Decreases upon Social Fear Expression, Related to Figure 3 We first examined the neuronal activity of WS neuron population. Scatterplot of the mean firing rates of individual WS neurons revealed a mixed modulation (Figure 3D). A subpopulation of WS neurons (42 out of 197, 21%) displayed a sustained firing increase when experimental mice confronted with a social stimulus (Video S3). Only a small proportion of neurons (12 out of 197, 6%) had an inhibitory response upon social risk assessment. The remainder maintained their activity level during fear expression. In comparison, a significantly smaller proportion of pyramidal neurons increased their firing rates upon approaching toward a social target in unconditioned control mice (control: 11%, 12 out of 109 recordings; conditioned: 21%, 42 out of 197 recordings, Fisher’s exact test, p < 0.05) (Figures 3D and 3H). The hyperactivity of dmPFC pyramidal neurons during social fear expression was further confirmed with a three-chamber testing paradigm (Figure S7). We next examined the neuronal activity of FS-PV population during social fear expression. Interestingly, in striking contrast to a mixed modulation property observed in WS neurons, the spiking activity declined almost for all FS-PV INs recorded, indicating that social fear expression suppressed FS-PV firing rate (Figure 3E; Video S4). Quantification of the mean discharge rates during social risk assessment confirmed the above observation as 84% of FS-PV INs (27 out of 32, green dots) displayed a significant decrease in firing rate upon social confrontation (Figure 3F). Because response properties were indistinguishable between putative FS-PV INs (n = 22) and opto-tagged FS-PV INs (n = 10), they were pooled for analysis. Instead of a consistent decrease in firing rate of majority of FS-PV INs observed in conditioned mice, the most FS-PV INs maintained their activity levels and a small proportion of neurons (33%, 4 out of 12) even increased their firing rates during social approach in unconditioned control animals (Figures 3I and 3J). Again, the decrease in FS-PV firing upon social approaches in conditioned mice was confirmed with a three-chamber testing paradigm (Figure S7). Therefore, FS-PV INs predominantly decreased their discharge rates upon social fear expression, suggesting a functional role of this IN population during social fear behavior. Abnormal hyperactivity of PFC is linked to fear states including social fear (Buff et al., 2016Buff C. Brinkmann L. Neumeister P. Feldker K. Heitmann C. Gathmann B. Andor T. Straube T. Specifically altered brain responses to threat in generalized anxiety disorder relative to social anxiety disorder and panic disorder.Neuroimage Clin. 2016; 12: 698-706Crossref PubMed Scopus (42) Google Scholar, Kawashima et al., 2016Kawashima C. Tanaka Y. Inoue A. Nakanishi M. Okamoto K. Maruyama Y. Oshita H. Ishitobi Y. Aizawa S. Masuda K. et al.Hyperfunction of left lateral prefrontal cortex and automatic thoughts in social anxiety disorder: A near-infrared spectroscopy study.J. Affect. Disord. 2016; 206: 256-260Crossref PubMed Scopus (14) Google Scholar). Consistently, our electrophysiological recordings revealed an elevated firing rate in a subset of dmPFC principal neurons during social fear expression (Figure 3). To know whether the enhanced dmPFC excitability was required for fear expression, we employed a pharmacogenetic approach to inactivate princi" @default.
• W2921744971 created "2019-03-22" @default.
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• W2921744971 date "2019-05-01" @default.
• W2921744971 modified "2023-10-17" @default.
• W2921744971 title "A Disinhibitory Microcircuit Mediates Conditioned Social Fear in the Prefrontal Cortex" @default.
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• W2921744971 doi "https://doi.org/10.1016/j.neuron.2019.02.026" @default.
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