Publications using TDT

Hearing loss is a pervasive global health challenge with profound impacts on communication, cognitive function, and quality of life. Recent studies have established age-related hearing loss as a significant risk factor for dementia, highlighting the importance of hearing loss research. Auditory brainstem responses (ABRs), which are electrophysiological recordings of acoustically evoked synchronized neural activity from the auditory nerve and brainstem, serve as in vivo correlates for sensory hair cell and synaptic function, hearing sensitivity, and other critical readouts of auditory pathway physiology, making them highly valuable for both basic neuroscience and clinical research. Despite the utility of the ABR, traditional ABR analyses rely heavily on subjective manual interpretation, which may introduce variability and pose challenges for reproducibility across studies. Here, we introduce Auditory Brainstem Response Analyzer (ABRA), a novel suite of open-source ABR analysis tools powered by deep learning, which automates and standardizes ABR waveform analysis. ABRA employs convolutional neural networks trained on diverse datasets collected from multiple experimental settings, achieving rapid and unbiased extraction of key ABR metrics, including peak amplitude, latency, and auditory threshold estimates. We demonstrate that ABRA’s deep learning models provide performance comparable to expert human annotators while dramatically reducing analysis time and enhancing reproducibility across datasets from different laboratories. By bridging hearing research, sensory neuroscience, and advanced computational techniques, ABRA facilitates broader interdisciplinary insights into auditory function. An online version of the tool is available for use at no cost at https://abra.ucsd.edu .

Spinal cord injury (SCI) remains a debilitating neurological disorder with limited therapeutic options, as existing treatments primarily address symptoms rather than address the complex interplay of cellular and molecular barriers to regeneration. These barriers collectively hinder functional recovery, including inhibitory glial scarring, chronic neuroinflammation, intrinsic neuronal regenerative deficits, and disruption of the blood-spinal cord barrier (BSCB). To address these limitations, we developed NanoScript-PTEN (NS-PTEN), a nonviral nanoparticle platform that delivers synthetic transcription factors to transiently suppress phosphatase and tensin homolog (PTEN) expression. PTEN negatively regulates the PI3K/AKT/mTOR signaling axis, which is a critical determinant of neuronal survival and axonal growth. By reducing PTEN levels, NS-PTEN derepresses this pro-survival pathway, promoting neuronal regeneration in the injured spinal cord. By integrating a DNA-binding domain targeting the PTEN promoter, a transcriptional repression module, and a nuclear localization signal onto a gold nanoparticle (AuNP) scaffold, NS-PTEN achieves transient control over PTEN repression, reactivating pro-regenerative signaling while minimizing the risks of tumorigenesis associated with permanent gene silencing. In a clinically relevant contusion SCI rat model, NS-PTEN induced a coordinated series of structural and microenvironmental improvements that collectively support spinal cord repair. Histologically, NS-PTEN enhanced axonal continuity and remyelination, as evidenced by denser NF-positive fibers and substantially greater MBP preservation than in both the injury and AuNP groups. Concurrently, NS-PTEN markedly attenuated astroglial and microglial reactivity, reducing GFAP+ border formation and diminishing Iba1+ inflammatory cell accumulation. At the vascular interface, NS-PTEN upregulated CD31 and occludin expression, indicating restored endothelial integrity and the reconstruction of tight junctions, which are critical for BSCB repair. In parallel, the inflammatory milieu shifted toward a regenerative phenotype, characterized by suppressed pro-inflammatory cytokine expression (IL-6, TNF-α, and iNOS) and elevated anti-inflammatory/neurotrophic factors (IL-10 and BDNF). These improvements are consistent with secondary, microenvironment-level benefits arising from acute neuronal PTEN repression rather than direct modification of non-neuronal cell types. Importantly, PTEN expression partially rebounded by DPI-28, aligning with the intended transient activity window of the nanoscript system and supporting its translational safety. Through this combination of precise, nonintegrative gene modulation and broad downstream remodeling, NS-PTEN addresses both intrinsic neuronal limitations and extrinsic inhibitory features of the SCI microenvironment.

In the mammalian cochlea upon acoustic stimulation, outer hair cells (OHCs) push and pull the basilar membrane, amplifying its vibration and therefore expanding the dynamic range of hearing. As a result, spiking patterns in auditory nerve fibers (ANFs) are believed to be significantly different, but how the central nervous system adapts to this substantial change is poorly understood. In this study, we took advantage of Prestin −/− mice of either sex where prestin, the motor protein in OHCs, was genetically knocked out, therefore removing cochlear amplification completely without changing the cellular structure of the cochlea significantly. While exocytosis from inner hair cells in the cochlea was largely intact, transmission at the endbulb of Held synapse between ANFs and bushy cells in the cochlear nucleus was significantly changed in Prestin −/− mice. Specifically, excitability of bushy cells was significantly increased, due to combination of slightly more depolarized resting membrane potential, increased membrane input resistance, and smaller and briefer afterhyperpolarization. Furthermore, synaptic strength was greatly reduced, caused by substantial decrease in the readily releasable pool (RRP) of synaptic vesicles. Significantly, paired-pulse plasticity at this synapse was reversed from depression in WT mice to facilitation in Prestin −/− mice, likely caused by quicker refilling of RRP observed in Prestin −/− mice. In conclusion, we found that transmission at the endbulb of Held synapse is significantly altered in absence of cochlear amplification, revealing interplay between the peripheral and central processing of auditory signals that contributes to expanded dynamic range of hearing seen in mammals and humans.

Avoiding actions with negative consequences is fundamental to adaptive behavior. Traditional theories suggest GABAergic inhibition of midbrain dopamine neurons, including those within ventral tegmental area (VTA DA ), mediate suppression of actions that lead to aversive outcomes. However, the role of dopamine inhibition in punishment learning remains unclear. To examine this, we conducted fiber photometry, pharmacological, and chemogenetic experiments in rats to measure VTA DA activity and GABA input across punishment learning, and test their causal contribution to behavior. VTA DA activity and GABA input phasically increased to response-elicited outcomes, with VTA DA activity being more strongly activated by rewards, while GABA input being more strongly activated by shock punishers during initial punishment. Pharmacologically blocking GABA A receptors in VTA or chemogenetically activating VTA DA neurons during initial, but not later, punishment sessions produced enduring deficits in punishment avoidance. These findings suggest long-term avoidance depends upon a critical window of GABA-mediated VTA DA inhibition during punishment learning.

Mutations in SLC26A4 are the second most common cause of hereditary hearing loss (HL) in many Asian countries, leading to DFNB4, a condition characterized by progressive HL and inner ear malformations. While gene therapy holds great potential, its postnatal application has remained unexplored because of the lack of suitable animal models and the challenges of prenatal intervention. To our knowledge, this study represents the first preclinical investigation of postnatal gene therapy for DFNB4 using a clinically relevant Slc26a4 -mutant mouse model that closely replicates human auditory phenotypes. Utilizing the synthetic AAV.Anc80L65 vector, we achieved robust SLC26A4 delivery to critical cochlear regions, including the endolymphatic sac and cochlear lateral wall. Comprehensive phenotypic analyses revealed a critical therapeutic window spanning the neonatal and juvenile stages, within which AAV.Anc80L65-mediated SLC26A4 delivery significantly improved hearing, as evidenced by lower auditory brainstem response thresholds. Moreover, the therapy preserved hair cells, reduced endolymphatic sac enlargement, partially restored the endocochlear potential, and mitigated inner ear structural degeneration. These therapeutic effects persisted into adulthood, highlighting the long-term efficacy of postnatal gene therapy. Together, these findings establish a critical therapeutic window for DFNB4 and demonstrate the feasibility of targeting the endolymphatic sac and cochlear lateral wall for effective intervention.

Cisplatin‐induced ototoxicity is a detrimental side effect of chemotherapy leading to hearing loss, for which no treatments are currently available. Despite the growing recognition of the endocannabinoid (eCB) system (ECS) as a significant contributor to different physiological and pathological processes, its role in hearing remains poorly investigated. To fill this knowledge gap, we performed a molecular profiling of the ECS in auditory hair cell (HC)‐like UB/OC1 cells derived from the mouse organ of Corti (OC), demonstrating the presence of the main eCBs‐binding receptors and metabolic enzymes along with the major eCBs ( N ‐arachidonoylethanolamine, AEA, and 2‐arachidonoylglycerol, 2‐AG) and additional eCB‐like compounds. Subsequently, we established an in vitro model of cisplatin‐induced ototoxicity, which was characterized by the downregulation of the HC marker myosin 7a (Myo 7a), and activation of nuclear factor kappa‐light‐chain‐enhancer of activated B‐cells (NF‐κB) associated with caspase‐3‐mediated cell death. In this model, we observed a downregulation of cannabinoid receptor 2 (CB 2 R), diacylglycerol lipase β (DAGLβ), and α/β hydrolase domain‐containing protein 6 (ABHD6), indicating a perturbation of the 2‐AG metabolic pathway. Furthermore, we validated the observed in vitro alterations in the OC of an in vivo model of cisplatin‐induced ototoxicity, thereby strengthening the physiological relevance of our findings. Finally, we demonstrated that pharmacological blockade of CB 2 R through SR144528 mitigates cisplatin‐induced HC damage via inhibition of caspase‐3 cleavage in UB/OC1 HC‐like cells, thereby providing novel mechanistic insights into the role of CB 2 R in ototoxicity. Overall, our study demonstrates the involvement of selective elements of the ECS in cisplatin‐induced ototoxicity, hence identifying novel potential biomolecular targets for chemotherapy‐related side effects.

Serotonin (5-hydroxytryptamine; 5HT) has long been considered anti-aggressive, but the mechanisms by which 5HT regulates downstream circuits to control aggression remain unclear. Combining fiber photometry, optogenetics, and miniaturized microscope recordings in double-transgenic male mice, we find that 5HT levels ramp up in the nucleus accumbens during aggression, inhibiting a subset of D1 medium spiny neurons to suppress attacks. Our results reveal a novel 5HT-mediated neuromodulatory mechanism for limiting aggressive behavior.

Norepinephrine (NE) is an important mediator of sympathetic activity that influences breathing. At the level of the inspiratory neural network, the preBötzinger complex (preBötC), NE modulation orchestrates changes in neuronal network dynamics that influence the stability of inspiratory rhythmogenesis. While this phenomenon has largely been attributed to NE-modulation of intrinsic excitability of inspiratory preBötC neurons, NE is also capable of modulating synaptic drive. Here, we resolve how NE affects synaptic properties and changes the activity dynamics of interconnected preBötC neurons in rhythmic brainstem slice preparations. Increased network burst amplitude and frequency coincided with enhanced inspiratory drive currents at the single neuron level. This increased drive was blocked by the NMDA receptor (NMDAR) antagonist, APV. Our in silico modeling indicated that synaptic calcium entry via NDMAR is key to maintaining network synchrony during this elevated state of excitability. This was consistent with our multi-electrode array studies revealing that NE-dependent NMDAR activity enhances and preserves synchrony during inspiratory network bursts. This synaptic mechanism may be a critical determinant for shaping inspiratory drive associated with changed neuromodulatory environments. Significance Statement This study demonstrates a previously undescribed synaptic mechanism by which noradrenergic modulation recruits NMDAR activity and shifts inspiratory network dynamics leading to a stable network state where synchronization is preserved among inspiratory neurons. This may be a critical mechanism preventing ventilatory instability when sympathetic activity is enhanced.

Animals must constantly scan their environment for imminent threats to their safety. However, they must also integrate their past experiences across long timescales to assess the potential recurrence of new threats. Though visual inputs are critical for the detection of environmental danger, whether and how visual information shapes an animal's assessment of whether a new threat is likely to reappear in a given context is unknown. In this work, we developed a behavioral assessment of long-term threat avoidance behavior where animals will avoid a familiar location where they previously experienced a single threat exposure. This avoidance behavior is highly sensitive and lasts for multiple days. Intriguingly, we find that the melanopsin-expressing, intrinsically photosensitive retinal ganglion cells tune this behavior via a perihabenula-nucleus accumbens circuit distinct from canonical visual threat detection circuits in male mice. These findings define a long-term threat avoidance behavior that is shaped by a defined retinal cell type based on prior experience.

Shaker‐1 mice carry a spontaneous missense mutation in Myo7a ( Myo7a Sh1 ) that interferes with the motor function of MYO7A. Mutation in the orthologous gene in humans causes syndromic (Usher 1B) or non‐syndromic forms of deafness. In hair cells, MYO7A is expressed throughout the stereocilia, where it has been implicated in tip‐link tensioning required for gating the mechanoelectrical transducer (MET) channel and setting its resting open probability ( P o ). The Myo7a Sh1 mutation progressively dysregulated the height of shorter stereocilia rows from the end of the first postnatal week onwards, associated with reduced MET current amplitude and hearing loss. Noise exposure exacerbated stereocilia dysfunction in Myo7a Sh1/Sh1 mice. Following the onset of maturation, hair cells from Myo7a Sh1/Sh1 mice showed normal resting P o and calcium sensitivity of the MET channel. In immature Myo7a Sh1/Sh1 hair cells, the resting P o was very small or absent in comparison to control cells, but it was restored by changing the membrane lipid bilayer fluidity or thickness by depleting cholesterol or PIP 2 . Bundle stiffness in immature IHCs was not affected by the absence of functional MYO7A but decreased after their onset of maturation in both genotypes. Expression of a subset of genes was affected similarly in immature Myo7a Sh1/Sh1 mice and in adult Myo7a conditional knockout mice, indicating a common response pathway in Myo7a ‐deficient mice. This study reveals that MET channel gating might differ depending on hair cell developmental stage, and MYO7A is likely to influence, albeit indirectly, force transmission via the lipid bilayer to the MET channel and maintenance of the shorter rows of transducing stereocilia. image Key points Shaker‐1 mice carry a spontaneous missense mutation in the shaker‐1 gene ( Myo7a Sh1 ) that interferes with the motor function of MYO7A, a protein expressed in hair‐cell stereocilia. The absence of functional MYO7A ( Myo7a Sh1/Sh1 mice) caused a progressive dysregulation in the height of the shortest two rows of stereocilia and the consequent loss of mechanoelectrical transduction (MET) current. Although immature hair cells from Myo7a Sh1/Sh1 mice exhibited a markedly reduced resting open probability of their MET channels, this was restored upon maturation or following depletion of cholesterol or PIP 2 from the lipid bilayer. Hair‐bundle stiffness was affected in immature inner hair cells from Myo7a Sh1/Sh1 mice, suggesting that MYO7A is not required for establishing the resting tension of the tip links gating the MET channels. We conclude that MYO7A is crucial for the structural integrity of the MET complex and transport of key proteins required to transfer forces efficiently from the lipid bilayer to the MET channel.

Objective: Perceived voice quality (VQ) ratings provide data with ordinal characteristics on arbitrary scales regarding the relative order of VQ disruptions ranging from mild to severe quality. The overarching goal of this research is to develop a new and rigorous method for perceptual evaluation of VQ using quantitative comparisons and facilitating standardized comparisons across time points, clinicians, and clinical sites. Our prior research developed standard ratio-level scales of breathy and rough VQ analogous to the sone scale that (a) have physical units, (b) are strongly related to psychophysical measures, and (c) can quantify not just the direction but also the magnitude of change. The current study reestablishes the standard reference points, validates the newly developed VQ scales with natural dysphonic stimuli, and evaluates the psychometric measurement properties of the novel scales for breathiness and roughness in a small clinical pilot experiment. Method: In the first experiment, a set of magnitude estimation (ME) tasks were first used to determine the perceived magnitudes of breathiness and roughness of 10 natural voice stimuli in each VQ continuum. The resulting data were compared with previously acquired magnitude estimates of the synthetic comparison stimuli to adjust the reference points. In the second experiment, a set of inexperienced listeners evaluated the same set of natural dysphonic stimuli using the new clinical scales with perceived magnitude expressed in standard VQ units. In the third experiment, two expert clinicians evaluated 12 breathy and 10 rough dysphonic voices (pre- and posttreatment) using the new VQ scales. Results: The standard reference units were identified as 15 dB SNR for breathiness and −26 dB modulation depth for roughness. The strength of the relationship between the ME data and the predicted values from the clinical scales was high for both breathiness and roughness ( r > .9). Treatment outcomes measured using the newly developed scales demonstrated high intra- ( r > .8) and interrater reliability ( r > .8) when compared to Consensus Auditory-Perceptual Evaluation of Voice providing evidence for concurrent validity of the clinical scales. Conclusion: Such formal VQ scales support valid quantitative comparisons of perceptual judgments and represent a critical step in clinical translation.

S ummary Although somatosensation is known to be important for precise hand control, how coordinated activity across sensory and motor cortical areas supports hand movements and object interactions is unclear. We simultaneously recorded neural activity from dorsal premotor cortex (PMd) and Area 2 of the primary somatosensory cortex in three rhesus macaques performing a reach-to-grasp task during recovery from a primary motor cortex (M1) lesion. Using dual-area latent factor analysis, we decomposed population activity into cross-area factors (CFs) shared between PMd and Area 2 and within-area factors (WFs) local to each region. Shared CFs tracked hand kinematics closely despite explaining less overall variance. Strikingly, the emergence of long-timescale, stereotyped sensory–motor cross-area dynamics was correlated with recovery of prehension and object grasping, whereas changes in within-area dynamics were not correlated with recovery. These findings suggest that restoration of coordinated sensory–motor population dynamics is important for recovery of skilled hand function after injury.

Neuropeptides like galanin are increasingly recognized as modulators of cognitive pathways. Galanin has been implicated in a wide range of pathological conditions in which frontal and temporal structures are compromised. Recently, we discovered that direct pharmacological stimulation of galanin receptor type 1 (GalR1) in the ventral prefrontal cortex (vPFC) and ventral hippocampus (vHC) caused opposing effects on attention and impulse control behaviors. In the present study, we investigate how neurons expressing GalR1 in these two areas differentially contribute to these behaviors. First, using multiplex fluorescent in situ-hybridization, we established that GalR1 is predominantly expressed in glutamatergic neurons in both the vPFC and vHC. Rats were assessed in their visuospatial attention and impulse control behaviors using the 5-Choice task. We developed a novel viral approach to gain genetic access to GalR1-expressing neurons in the vPFC and vHC and found that optogenetic excitation of GalR1 expressing neurons in the vPFC, but not vHC, selectively disrupted attention. Finally, using fiber photometry, we measured bulk calcium dynamics in GalR1-expressing neurons and discovered that GalR1- expressing neurons in the vPFC and vHC showed opposing activity; increased activity in neurons in the vPFC corresponded to correct, attentive actions, whereas activity in the vHC was associated with errors. This region- and response-specific intrinsic activity of galanin, mediated by subclasses of neurons in frontotemporal circuitry participates in shaping the expression of executive-control behaviors that often go awry in various disorders of mental health.

Brain systems mediating responses to previously encountered threats provide critical survival functions. Fear memory and extinction are underpinned by neural representations in the basolateral amygdala (BLA) 1–7 , but the contribution of non-neuronal cells, including astrocytes, to these processes remains unresolved. Here, using in vivo calcium (Ca 2+ ) imaging and causal astrocyte manipulations, we find that BLA astrocytes dynamically track fear state and support fear memory retrieval and extinction. By combining astrocyte manipulations with in vivo BLA neuronal Ca 2+ imaging and electrophysiological recordings, we show that astrocyte Ca 2+ signalling enables neuronal encoding of fear memory retrieval and extinction, and readout through a BLA–prefrontal circuit. Our findings reveal a key role for astrocytes in the generation and adaptation of fear-state-related neural representations, revising neurocentric models of critical amygdala-mediated adaptive functions.

Binaural cues are crucial for sound localization, and understanding the neural mechanisms of binaural sound processing gives important insights into how receivers localize signalers, which in anurans is a key component of mate selection. We characterized the binaural interaction component (BIC) by collecting monaural and binaural auditory brainstem responses (ABR) using click stimuli with varying interaural time difference (ITD) and interaural level difference (ILD) in male and female Cope’s gray treefrogs ( Hyla chrysoscelis ). We hypothesized that the latency of the BIC peaks would increase with larger ITDs and ILDs. We also hypothesized that females would show a stronger relationship between binaural cues and BIC characteristics than males because of the greater importance of directional hearing for females. We characterized two prominent BIC peaks, DN1 and DN2. Both BIC peak latencies had a positive relationship with ITD, but there was no effect of ITD on peak amplitudes. The amplitude and latency of the BIC peaks were not affected by variation in ILD. There were no sex or body size effects on ABR characteristics including BIC characteristics or the effects of ITD or ILD on the BIC. Our findings demonstrate that the BIC is driven primarily by ITD in H. chrysoscelis . This is the first study to characterize the BIC in an amphibian, which expands the comparative understanding of the neural mechanisms of binaural hearing in vertebrates.

Cell types are the basic units of the cerebral cortex. Broad and narrow spike waveforms (BW and NW) are the primary criteria for classifying putative excitatory and inhibitory cortical neurons, particularly in non-human primates where genetic accessibility is limited. We have classified cell types in the auditory cortex of marmosets using spike waveforms and firing patterns and identified a new type of neuron: the NW-burst neuron. NW-burst neurons are excitatory, as they drive but do not suppress the firing of connected neurons. Furthermore, NW-burst neurons displayed shorter response latencies, lower response variability, smaller receptive fields, stronger correlations between spatial and non-spatial selectivity, and higher decoding accuracy than other neurons. Together, these findings suggest that cortical NW-burst neurons in non-human primates represent a distinct excitatory cell type. Significance Statement Classifying cell types in non-human primates is challenging due to limited genetic tools. Traditionally, neurons with narrow spikes are assumed to be inhibitory. Challenging this view, we analyzed 1,816 high-quality single units in the marmoset auditory cortex and discovered that narrow-spike burst-firing neurons were excitatory. These neurons exhibited shorter response latencies, smaller receptive fields, and higher decoding accuracy. Crucially, they showed a positive correlation between "where" and "what" selectivity, defying the standard trade-off between spatial and non-spatial response properties. These findings reveal a specific excitatory cell type in the auditory cortex of a non-human primate species that integrates sound information with high temporal fidelity and feature selectivity.

The nucleus accumbens (NAc) is a critical node in the neural circuitry underlying reward and motivated behavior, including hedonic feeding, and its dysfunction is implicated in maladaptive behaviors in numerous psychiatric disorders. Medium spiny neurons (MSNs) in the NAc are predominantly categorized into dopamine 1 receptor-expressing (D1-MSNs) and dopamine 2 receptor-expressing (D2-MSNs) subtypes, which are thought to exert distinct and sometimes opposing roles in reward-related processes. Here, we used optogenetic, chemogenetic, and fiber photometry approaches in Cre driver mouse lines to dissect the causal contributions of D1- and D2-MSNs to the consumption of a high-fat diet (HFD) in sated animals. Activation of D1-MSNs via optogenetics or DREADDs significantly suppressed high-fat intake, whereas inhibition of these neurons increased consumption only in male but not female mice. Conversely, activation of D2-MSNs enhanced high-fat intake only in females, while their inhibition reduced intake in both sexes. Fiber photometry revealed dynamic shifts in D2-MSN activity over repeated high-fat exposures, with increasing activity correlating with escalating intake of HFD only in female mice. These results highlight opposing contributions of D1- and D2-MSN populations in regulating hedonic feeding and support a model in which salience and consumption are modulated by NAc MSN subtype-specific activity in a sex-specific manner. Understanding this circuitry has implications for the development of tailored treatment strategies for obesity and other disorders of compulsive consumption.

Objectives The aim of this study was to investigate the changes in Epac1 and ferroptosis‐related proteins in aged mice and the House Ear Institute‐Organ of Corti 1 (HEI‐OC1) cells, with the goal of elucidating their potential role in age‐related hearing loss. Methods The expression of Epac1 in the cochlea of C57BL/6J mice was examined by using immunofluorescence staining and Western blot analysis. To further verify the role of Epac1 in age‐related hearing loss, small interfering RNA (siRNA) was transfected into HEI‐OC1 cells, resulting in the downregulation of Epac1. Results The results revealed a decrease in Epac1 expression in the cochlea of aged mice. After downregulating the level of Epac1 in vitro, a greater level of ferroptosis was observed, and the aging process was accelerated. Conclusions Epac1 plays a crucial role in the aging process of auditory hair cells via ferroptosis.

The bed nuclei of the stria terminalis (BST) is a nuclear complex that coordinates neuroendocrine, autonomic, and behavioral responses associated with maintaining homeostasis. Here, we demonstrate that melanocortin 3 receptor (MC3R) neurons in the BST (BST MC3R ) play a key role in modulating feeding behaviors and responses to stressful events. BST MC3R neurons are primarily GABAergic and colocalize with neuropeptides known to regulate feeding and affective behaviors. Chemogenetic activation of BST MC3R neurons causes reduced feeding, particularly in males. BST MC3R neurons are also robustly activated by stress and can control responses to stress and defensive behaviors in both sexes. Whole-brain monosynaptic rabies tracing identified multiple sexually dimorphic inputs to BST MC3R neurons that may contribute to observed functional sexual dimorphisms. Altogether, these data reveal that BST MC3R neurons participate in sexually dimorphic circuits that influence feeding and defensive behaviors, responses to stress, and may represent a potential therapeutic target for stress- and eating-related disorders.

The ability for an organism to encode fear memories is necessary for survival. Once a threat is no longer present, organisms must suppress, or extinguish, this fear memory in favor of other adaptive behaviors. In rodents, the infralimbic cortex (IL) is a locus critical for the extinction of cued fear memory. While this role has been known for decades, the circuit mechanisms underlying its recruitment are largely unknown. By using a combination of immunohistochemistry, neural tagging, in vivo calcium imaging and optogenetics, and optogenetics-assisted brain slice electrophysiology, we revealed that the dynamic activity and plasticity of IL inhibitory interneurons is critical for encoding fear extinction. Specifically, after fear conditioning, IL parvalbumin interneurons exhibit increased activity and plasticity, driving enhanced freezing. After fear extinction, however, IL somatostatin interneurons exhibit extinction cue-associated activity and plasticity, and their activity facilitates extinction memory encoding through inhibition of parvalbumin interneuron activity and disinhibition of IL principal neurons. Further, glutamatergic projections from the basolateral amygdala undergo experience- and cell type-specific plasticity that is required to drive the dynamic recruitment of IL parvalbumin and somatostatin interneurons after fear conditioning and extinction, respectively. Overall, these results reveal the mechanisms of cued fear extinction encoding and highlight critical roles for local IL microcircuit computations in these roles.