Behavioral Neuroscience publications

Recent work shows that the brain’s arousal system remains active during sleep, with rhythmic locus coeruleus (LC) activity shaping sleep architecture and supporting memory consolidation. The LC releases norepinephrine (NE) in infraslow (~0.02 Hz) bouts that gate NREM sleep spindles. Here, we demonstrate that heart rate (HR) fluctuations during NREM are tightly phase-locked to these NE rhythms, identifying the LC as a key driver of very-low-frequency HR variability (VLF-HRV), an understudied autonomic signal. Using optogenetics, transient LC inhibition blunts HR slowing, whereas LC activation produces rapid HR acceleration, demonstrating a direct LC-HR relationship during sleep that is maintained across a defined range of LC activity levels but breaks down when LC activity becomes excessive. We further show that infraslow HR variability is a cross-species marker of spindle-dependent memory processing. In mice, the amplitude of HR decelerations during NREM correlates with spindle activity and subsequent memory performance. Remarkably, human sleepers show the same pattern: stronger VLF-HR fluctuations during NREM correspond to increased spindle expression and better overnight memory retention. These findings reveal a mechanistic pathway through which graded changes in LC activity, up to a critical level, modulates autonomic physiology during sleep and identify infraslow HR variability as a non-invasive marker of brainstem function and memory-promoting sleep. Because LC degeneration occurs early in neurodegenerative disease, sleep-derived HR metrics may provide a scalable indicator of emerging neuromodulatory dysfunction.

The ability to detect deviations from expected sensory input is fundamental for adaptive behavior. We recorded electrocorticographic activity from the auditory (AC) and prefrontal (PFC) cortices of behaving macaques during an auditory oddball task to probe the cortical dynamics of predictive processing. Repetition of standard stimuli evoked suppression and facilitation in AC and strong low-frequency (2 Hz) enhancement in PFC, accompanied by bidirectional delta-band GC-defined interactions indicative of a shared predictive state. Deviant stimuli triggered earlier AC responses followed by PFC activation and increased GC-defined directed interactions across theta, alpha, and conventional gamma bands. Behavioral engagement amplified both repetition-related and deviance-related ECoG responses, strengthening cortical network coordination. Together, these findings reveal behaviorally gated auditory–prefrontal dynamics that are consistent with hierarchical predictive-processing accounts, while also allowing for contributions from repetition-, novelty-, and salience-related mechanisms.

Social recognition, the ability to distinguish between individuals, is essential for cognitively demanding social behaviors. The anterior olfactory nucleus (AON), a primary olfactory cortical region, is implicated in this process, but the underlying neurocircuitry remains poorly understood. Here, we generated a novel mouse line to enable genetic access to AON pyramidal neurons and mapped their whole-brain synaptic inputs and outputs. The medial prefrontal cortex (mPFC), a crucial hub for social cognition, is the primary neocortical target of AON neurons, which form monosynaptic excitatory connections with a substantial fraction of mPFC neurons. The AONmPFC pathway is activated during social investigation, and chemogenetic inhibition of this pathway impairs social recognition. Moreover, an analogous AON-prefrontal pathway is present in humans, as supported by resting-state functional magnetic resonance imaging (fMRI) functional connectivity analyses. Taken together, these findings reveal a conserved olfactory-prefrontal circuit spanning mice to humans, potentially linking olfactory dysfunction to neuropsychiatric disorders.

How positive and negative affective stimuli interact in the brain to influence behavioral outcomes remains poorly understood. Here, we show that recall of a positively valenced reward-associated cue (reward-conditioned stimulus, CS Rew +) can prevent or reverse fear generalization in mice. Modification of generalized fear by recall of a CS Rew + is dependent on the midbrain dopamine system and the regulation of discriminatory fear encoding by the central amygdala (CeA). Precisely timed, transient elevations in dopamine are necessary to reverse fear generalization and nondiscriminatory fear encoding in the CeA. Recall of a positive association is also effective at enhancing the extinction of a conditioned fear response in a dopamine-dependent manner. These data demonstrate that recall of a positive experience can be an effective means to suppress generalized fear and show that dopamine projections to the CeA are an important neural substrate for this phenomenon.

Foraging in the wild requires coordinated switching of critical functions, including goal-oriented navigation and context-appropriate action selection. Nevertheless, few studies have examined how different functions are represented in the brain during naturalistic foraging. To address this question, we recorded multiple single-unit activities from the medial prefrontal cortex (mPFC) of rats seeking a sucrose reward in the presence of an unpredictable attack posed by a robotic predator (Lobsterbot). Simultaneously recorded ensemble activities from neurons were analyzed in reference to various behavioral indices as the animal moved freely across the foraging area (F) between the nest (N) and the goal (E) area. An artificial neural network, trained with simultaneously recorded neural activity, estimated the rat’s current distance from the Lobsterbot. The accuracy of distance estimation was the highest in the middle F-zone in which the dominant behavior was active navigation. The spatial encoding persisted in the N-zone when non-navigational behaviors such as grooming, rearing, and sniffing were excluded. In contrast, the accuracy decreased as the animal approached the E-zone, when the activity of the same neuronal ensembles was more correlated with events related to dynamic decision-making between food procurement and Lobsterbot evasion. A population-wide analysis confirmed highly heterogeneous encoding by the region. To further assess the decision-related activity in the E-zone, a naive Bayesian classifier was trained to predict the success and failure of avoidance behavior. The classifier predicted the avoidance outcome as much as 6 s before the head withdrawal. In addition, two sub-populations of recorded units with distinct temporal dynamics contributed differently to the prediction. These findings suggest that an overlapping population of mPFC neurons may switch between two heterogeneous modes, encoding relevant locations for goal-directed navigation or an imminent situational challenge.

Memory consolidation enables animals to draw on past experiences to guide future behavior. This process involves system- and synaptic-level changes and predominantly occurs during sleep. While hippocampal-cortical circuits are well studied in this context, the contributions of other systems, including dopaminergic circuits—key players in learning-related processes—remain poorly understood. Ventral tegmental area dopaminergic (VTA DA ) neurons are active during sleep and suggested to participate in memory consolidation processes; however, causal evidence for this is lacking. Using calcium-dependent fiber photometry, electrophysiology, and chemogenetic and optogenetic manipulations across learning paradigms, we explore the functions of VTA DA neuronal activity during sleep. We show that VTA DA activity during nonrapid eye movement sleep is experience dependent, is enhanced by motor skill and associative learning, facilitates motor skill memory consolidation, and exhibits a motor learning–dependent increase in temporal coordination with cortical spindle oscillations. Our findings uncover a previously unidentified function for VTA DA neurons in consolidating memories during sleep, advancing understanding of this central neuromodulator’s functions in regulating fundamental biological processes.

The anterior-lateral motor cortex (ALM) has been extensively studied as a model for understanding the cortical mechanisms involved in planning directional movements. ALM neurons show preparatory activity that predict whether the mouse will produce a left- or right-directed lick. While the neural mechanisms underlying ALM dynamics and their links to behavior are beginning to be elucidated, the sources of this directional activity remain unclear. Here, we examined the role of ALM dopaminergic circuits in mice performing a directional licking task. We report that dopamine (DA) signals and the activity of neurons expressing D1 receptors (D1R + ) tracked the preparation and execution of licking and demonstrated a bias for planning of licks aimed at the direction contralateral to the recording site. Unilateral optogenetic manipulations of D1R + neurons or DA afferents affected lateral licking in a way consistent with their role in planning contralateral movements. Together, these results show that cortical DA modulation plays an important role in the motor preparation of directional movements.

Introduction The posterior tail of the striatum receives dense inputs from sensory regions of cortex and thalamus, as well as midbrain dopaminergic innervation, providing a neural substrate for associative sensory learning. Previously, we have demonstrated that developmental hearing loss is associated with aberrant physiological states in striatal medium spiny neurons (MSNs). Methods Here we directly investigated auditory associative learning impairments in the striatum of adult Mongolian gerbils that underwent transient developmental hearing loss or sham hearing loss during the critical period of auditory development. We used electrophysiology to reveal significant changes to neuronal population responses in vivo and intrinsic and synaptic properties to medium spiny neurons in vitro as animals learned an appetitive “Go/No-Go” auditory discrimination task. For in vivo experiments a 64-channel electrode was implanted in the auditory region of the posterior tail of the striatum and neuronal recordings were carried out as animals learned the task. For in vitro experiments, corticostriatal slice preparations were made from animals on each day of training. Results In naïve animals from both groups there was limited to no phase locking to either auditory stimulus in vivo , and long term depression resulted from theta burst stimulation in vitro . Furthermore, intrinsic and synaptic properties in normal hearing animals were unaffected; however, the hearing loss group continued to show lowered synaptic inhibition, synaptic hyperexcitation, and suppressed intrinsic excitability in the hearing loss group. Starting around day 3–4 in both groups, the emergence of striatal medium spiny neuron phase locking to the auditory conditioning stimuli was observed in vivo . This occurred contemporaneous to an increased probability of theta burst induced LTP during MSN whole cell recording in vitro , and acquisition of the task as the correct rejection response significantly increased in the behaving animals. During the acquisition phase MSNs in the normal hearing group showed a significant decrease in synaptic inhibition and increase in synaptic excitation with no change to intrinsic excitability, while the MSNs in the hearing loss group showed a significant increase in synaptic inhibition, reduction of synaptic hyper excitability, and compensatory changes to intrinsic excitability that supported normal action potential generation. In both groups, synaptic properties were resolved to similar level of E/I balance that could be part of a conserved learning state. Discussion These changes to the intrinsic and synaptic properties likely support LTP induction in vivo and the strengthening of synapses between auditory inputs and MSNs that facilitate neuronal phase locking. These findings have significant implications for our understanding of striatal resilience to sensory impairments in early life, in addition to establishing a granular understanding of the striatal circuit changes that support reward driven stimulus–response learning.

In many mammalian species, female behavior towards infant conspecifics changes across reproductive stages. Sexually naïve females interact minimally or aggressively with infants, whereas the same animals exhibit extensive care behavior, even towards unrelated infants, after parturition1–6. Here, we discovered that two distinct sets of serotonin neurons collectively mediate this dramatic transition in maternal behavior—serotonin neurons projecting to the medial preoptic area (mPOA) promote pup care in mothers, whereas those projecting to the bed nucleus of the stria terminalis (BNST) suppress pup interaction in virgin female mice. Disrupting serotonin synthesis in either of these subpopulations or stimulating either subpopulation is sufficient to toggle pup-directed behavior between that displayed by virgin females and that of lactating mothers. In virgin female mice, the first pup interaction triggers an increase in serotonin release in BNST but a decrease in mPOA. In mothers, serotonin activity becomes greatly elevated in mPOA during pup interactions. Acute interruption of serotonin signaling locally in either mPOA or BNST disrupts the stage-dependent switch in pup care. Together, these results highlight how functionally distinct serotonin subpopulations orchestrate social behaviors appropriate for a given reproductive state, and suggest a circuit logic for how a neuromodulator coordinates adaptive behavioral changes across life stages.

Dopamine (DA)-producing neurons of the ventral tegmental area (VTA) regulate consummatory behavior in a state-dependent manner (e.g. when hungry or thirsty). The mechanisms by which and extent to which DA neurons are regulated by these interoceptive signals are poorly understood. Here, we identify transient receptor potential canonical type 6 (TRPC6) channels as selective mediators of neuropeptide receptor-induced calcium signaling in VTA-DA neurons. These channels regulate DA neuron activity and consummatory behavior in a state-dependent manner. We find that TRPC6 channels regulate distinct aspects of neuropeptide-induced calcium signals in DA neurons but make little contribution to calcium dynamics associated with metabotropic neurotransmitter receptor signaling. We further show that TRPC6 channels regulate scalable reward valuation and consummatory behavior in hungry but not thirsty mice. These findings demonstrate that neuropeptide-and neurotransmitter-activated G-protein coupled receptors (GPCRs) regulate cellular calcium dynamics through distinct mechanisms, and that TRPC6 channels are important determinants of how animals respond to different homeostatic demands.

Atypical sensory processing, particularly in the auditory domain, is one of the most common and quality-of-life affecting symptoms seen in autism spectrum disorders (ASD). Fragile X Syndrome (FXS) is a leading inherited cause of ASD and a majority of FXS individuals present with auditory processing alterations. While auditory hypersensitivity is a common phenotype observed in FXS and Fmr1 knockout (KO) rodent models, it is important to consider other auditory coding impairments that could contribute to sound processing difficulties and disrupted language comprehension in FXS. We have shown previously that a Fmr1 KO rat model of FXS exhibits heightened sound sensitivity that coincided with abnormal perceptual integration of stimulus bandwidth, indicative of altered spectral processing. Frequency discrimination is a fundamental aspect of sound encoding that is important for a range of auditory processes, such as source segregation and speech comprehension, and disrupted frequency coding could thus contribute to a range of auditory issues in FXS and ASD. Here we explicitly characterized spectral processing deficits in male Fmr1 KO rats using an operant conditioning tone discrimination assay and in vivo electrophysiological recordings from the auditory cortex and inferior colliculus. We found that Fmr1 KO rats exhibited poorer frequency resolution, which corresponded with neuronal hyperactivity and broader frequency tuning in auditory cortical but not collicular neurons. Using an experimentally informed population model, we show that these cortical physiological differences can recapitulate the observed behavior discrimination deficits, with decoder performance being tightly linked to differences in cortical tuning width and signal-to-noise ratios. Together, these findings indicate that cortical hyperexcitability in Fmr1 KO rats may act to preserve signal-to-noise ratios and signal detection threshold at the expense of sound sensitivity and fine feature discrimination, highlighting a potential mechanistic locus for a range of auditory behavioral phenotypes in FXS.

Affective and consumption circuits in the brain are intertwined, with changes in each domain often affecting the other. Therapeutic interventions that reduce consumption, thereby facilitating weight loss, have tended to increase anxiety and depression. Obesity is a major risk factor for poor health; thus, it is important to understand the circuits and signals that regulate consummatory and affective behavior. Neurons expressing Urocortin-1 (Ucn) in the Edinger-Westphal (EW) nucleus have been hypothesized to play an important role in regulating both consummatory and affective behavioral domains and responses to stress. We generated UcnCre mice to allow measurement of Ucn neuron calcium activity and to directly activate these neurons during consummatory behaviors and repeated restraint stress. Our findings provide evidence for Ucn neuron regulation of consummatory behaviors and some affective behaviors.

Although control of movement involves many cortical association areas, bidirectional brain-machine interfaces (BMIs) typically decode movement intent from the motor cortex and deliver feedback information to the primary somatosensory cortex (S1). Compared to the S1, the parietal and premotor areas encode more complex information about object properties, hand pre-shaping, and reach trajectories. BMIs therefore might deliver richer information to those cortical association areas than to primary areas. Here, we investigated whether instructions for a center-out task could be delivered via intracortical microstimulation (ICMS) in the anterior intraparietal area (AIP), dorsal posterior parietal cortex (dPPC), or dorsal premotor cortex (PMd) as well as the ventral premotor cortex (PMv) and S1. Two monkeys successfully learned to use AIP, PMv, or S1-ICMS instructions, but neither learned to use dPPC- or PMd-ICMS instructions. The AIP, PMv, and S1 may thus be effective cortical territory for delivering information to the brain, whereas the dPPC or PMd may be comparatively ineffective.

Introduction Tinnitus is the perception of non-meaningful sound in the absence of external stimuli. Although tinnitus behavior in animal models is associated with altered central nervous system activity, it is not currently possible to identify tinnitus using neuronal activity alone. In the mouse inferior colliculus (IC), a subpopulation of neurons demonstrates a sustained increase in spontaneous activity after a long-duration sound (LDS). Methods Here, we use the “ LDS test ” to reveal tinnitus-specific differences in sound-evoked plasticity through IC extracellular recordings and the auditory brainstem response (ABR LDS ) in CBA/CaJ mice after sound exposure and behavioral tinnitus assessment. Results Sound-exposed mice showed stronger and shorter tone-evoked responses in the IC compared to unexposed controls, but these differences were not strong predictors of tinnitus. In contrast, in the LDS test, non-tinnitus mice had a significantly stronger suppression in tone-evoked spike rate compared to tinnitus and unexposed control mice. ABR peak amplitudes also revealed robust differences between tinnitus and non-tinnitus mice, with ABR peaks from non-tinnitus mice exhibiting significantly stronger suppression in the LDS test compared to tinnitus and control mice. No significant differences were seen between cohorts in ABR amplitude, latency, wave V:I ratio, wave V:III ratio, I-V intra-peak latency, and I-VI intra-peak latency. We found high-frequency tone stimuli better suited to reveal tinnitus-specific differences for both extracellular IC and ABR recordings. Discussion We successfully used the LDS test to demonstrate that tinnitus-specific differences in sound-evoked plasticity can be shown using both multi-unit near-field recordings in the IC and non-invasive far-field recordings, providing a foundation for future electrophysiological research into the causes and treatment of tinnitus.

Noise exposure is one of the most common causes of hearing loss and hyperacusis. Studies have shown that noise exposure can induce a cortical gain to compensate for reduced input of the cochlea, which may contribute to the increased sound sensitivity. However, many people with hyperacusis have no measurable cochlear lesion after being exposed to loud sound. In this experiment, we studied the neurological alterations in the cortical and subcortical areas following a prolonged moderate level of noise exposure (84 dB SPL, 8 h/day for 4 weeks) in the laboratory mice. The cochlear function was monitored by auditory brainstem responses (ABRs). The behavioral auditory sensitivity and temporal processing were evaluated using the acoustic startle response (ASR) and gap‐induced prepulse inhibition (gap‐PPI). The central auditory functions were determined by electrophysiological recordings of the inferior colliculus (IC) and the auditory cortex (AC). Our results showed that although there was no significant difference in the ABR thresholds, the noise group showed enhanced ASR and gap‐PPI compared to the control group. Increased neural activity in both the IC and the AC was recorded in the noise‐exposed mice compared to the control group, suggesting a central gain in both the subcortical and cortical regions. The current source density (CSD) analysis of the AC response revealed an increased columnar excitation and reduced corticocortical projection in the noise group, different from the central gain model of noise‐induced hearing loss. Our results suggest that chronic “nondestructive” noise can increase the gain of the central auditory system by altering the balance of auditory thalamocortical and intracortical inputs, which may contribute to the increased sound sensitivity in people with normal hearing.

Medial Forebrain Bundle Deep Brain Stimulation (MFB‐DBS) can have rapid and long lasting antidepressant effects in Treatment Resistant Depression (TRD) patients. The mechanisms are not well understood, but one hypothesis stipulates that modulation of the dopaminergic (DAergic) fibers contribute to the therapeutic outcome. Acute DBS effects on DA release have been studied; however, longitudinal studies with acute‐repetitive DBS are lacking. Long‐Evans accumbal DA release and Ventral Tegmental Area (VTA) calcium tonic and phasic signaling to different mfb‐DBS parameters were measured using fiber photometry over 8 weeks, following acute and repetitive stimulation in behaving and non‐behaving animals. DBS‐induced release was observed in both targets, with increased frequency and DBS duration. 130 Hz stimulation increased phasic and tonic DA response over time, with the latter being a potential mechanism for its long‐term clinical effectiveness. VTA calcium transients decreased, while phasic activity increased with frequency. Pulse width (PW)‐mediated differential peak release timing also suggests potential parallel activation of diverse fiber types. Additionally, decreased DA transients rate during Elevated Plus Maze (EPM) suggests context and stimulation duration‐dependent DA release. The data confirm chronic antidromic/orthodromic DAergic responses with stimulation parameter dependent variability, providing novel insights into temporal adaptations, connectivity and fiber recruitment on mfb DBS. image

Psychedelics have experienced renewed interest following positive clinical effects, however the neurobiological mechanisms underlying effects remain unclear. The paraventricular nucleus of the hypothalamus (PVN) plays an integral role in stress response, autonomic function, social behavior, and other affective processes. We investigated the effect of psilocin, the psychoactive metabolite of psilocybin, on PVN reactivity in Sprague Dawley rats. Psilocin increased stimulus-independent PVN activity as measured by c-Fos expression in male and female rats. Psilocin increased PVN reactivity to an aversive air-puff stimulus in males but not females. Reactivity was restored at 2- and 7-days post-injection with no group differences. Additionally, prior psilocin injection did not affect PVN reactivity following acute restraint stress. Experimental groups sub-classified by baseline threat responding indicate that increased male PVN reactivity is driven by active threat responders. These findings identify the PVN as a significant site of psychedelic drug action with implications for threat responding behavior.

Introduction Subjective tinnitus, the perception of sound without an external acoustic source, is often subsequent to noise-induced hearing loss or ototoxic medications. The condition is believed to result from neuroplastic alterations in the auditory centers, characterized by heightened spontaneous neural activities and increased synchrony due to an imbalance between excitation and inhibition. However, the role of the thalamic reticular nucleus (TRN), a structure composed exclusively of GABAergic neurons involved in thalamocortical oscillations, in the pathogenesis of tinnitus remains largely unexplored. Methods We induced tinnitus in mice using sodium salicylate and assessed tinnitus-like behaviors using the Gap Pre-Pulse Inhibition of the Acoustic Startle (GPIAS) paradigm. We utilized combined viral tracing techniques to identify the neural circuitry involved and employed immunofluorescence and confocal imaging to determine cell types and activated neurons. Results Salicylate-treated mice exhibited tinnitus-like behaviors. Our tracing clearly delineated the inputs and outputs of the auditory-specific TRN. We discovered that chemogenetic activation of the auditory TRN significantly reduced the salicylate-evoked rise in c-Fos expression in the auditory cortex. Discussion This finding posits the TRN as a potential modulatory target for tinnitus treatment. Furthermore, the mapped sensory inputs to the auditory TRN suggest possibilities for employing optogenetic or sensory stimulations to manipulate thalamocortical activities. The precise mapping of the auditory TRN-mediated neural pathways offers a promising avenue for designing targeted interventions to alleviate tinnitus symptoms.

Hearing loss can lead to long-lasting effects on the central nervous system, and current therapies, such as auditory training and rehabilitation, show mixed success in improving perception and speech comprehension. Vagus nerve stimulation (VNS) is an adjunctive therapy that can be paired with rehabilitation to facilitate behavioral recovery after neural injury. However, VNS for auditory recovery has not been tested after severe hearing loss or significant damage to peripheral receptors. This study investigated the utility of pairing VNS with passive or active auditory rehabilitation in a rat model of noise-induced hearing loss. Although auditory rehabilitation helped rats improve their frequency discrimination, learn novel speech discrimination tasks, and achieve speech-in-noise performance similar to normal hearing controls, VNS did not enhance recovery of speech sound perception. These results highlight the limitations of VNS as an adjunctive therapy for hearing loss rehabilitation and suggest that optimal benefits from neuromodulation may require restored peripheral signaling.

The hearing abilities of mammals are impacted by factors such as social cues, habitat, and physical characteristics. Despite being used commonly to study social behaviors, hearing of the monogamous prairie vole (Microtus ochrogaster) has never been characterized. In this study, anatomical features are measured and auditory brainstem responses (ABRs) are used to measure auditory capabilities of prairie voles, characterizing monaural and binaural hearing and hearing range. Sexually naive male and female voles were measured to characterize differences due to sex. It was found that prairie voles show a hearing range with greatest sensitivity between 8 and 32 kHz, binaural hearing across interaural time difference ranges appropriate for their head sizes. No differences are shown between the sexes in binaural hearing or hearing range (except at 1 kHz), however, female voles have increased amplitude of peripheral ABR waves I and II and longer latency of waves III and IV compared to males. The results confirm that prairie voles have a broad hearing range, binaural hearing consistent with rodents of similar size, and differences in amplitudes and thresholds of monaural physiological measures between the sexes. These data further highlight the necessity to understand sex-specific differences in neural processing that may underly variability in responses between sexes.