Behavioral Neuroscience publications

Interpersonal coordination is fundamental to social evolution. We investigate its phenomenology and neural underpinnings in humans and macaques, examining the behavioral adaptations required for mutual coordination during motor interactions and the extent to which the underlying brain mechanisms are shared across species. Using a common interpersonal coordination paradigm, we conducted functional magnetic resonance imaging (fMRI) in humans and intracranial local field potential (LFP) recordings in macaques. Despite between-species behavioral discrepancies, both monkeys and humans coordinate through adjustments that proved to be based on proactive adaptation of motor planning and execution. Evidence from fMRI and time-resolved decoding analysis of LFPs converged to show modulation of premotor brain activity associated with interpersonal coordination and its effectiveness. Moreover, a dynamic sequential coding emerged, whereby the action context is represented early during planning, and coordination features near movement onset. Our findings reveal an evolutionarily conserved cortical architecture across primates that supports cooperative motor behavior.

Spatial disorientation is emerging as an early cognitive biomarker of dementia, but the underlying neural mechanisms remain undefined. The anterodorsal nucleus of the thalamus (ADn) exhibits early and selective vulnerability to pathological misfolded forms of tau, a major hallmark of Alzheimer's disease. As the ADn contains a high density of head direction (HD) cells, we hypothesized that ptau disrupts HD cell activity, promoting spatial disorientation. To test this, we virally expressed human mutant tau in the ADn of adult wild-type and C1ql2-Cre mice. ADn-tau mice were defined by phosphorylated and oligomeric forms of tau in ADn somata and axon terminals. During initial spatial learning, ADn-tau mice exhibited increased looping behavior, indicative of spatial disorientation. Using in vivo extracellular recordings, we found that ADn cells had reduced directionality, lower directional coherence, and altered burst firing. These findings suggest that early alterations in HD signaling are predictive of future cognitive decline.

Impulsivity is a core pathological feature of various psychiatric disorders including obsessive‐compulsive disorder, attention‐deficit/hyperactivity disorder, and schizophrenia, which is conceptualized as dysregulated motivational and inhibitory processes. However, the underlying neural mechanism is poorly known. Using an olfactory cued Go/No‐Go task, this work finds increased false alarm rate, shortened licking onset latency, elevated licking frequency and reduced inter‐trial consistency in mice treated by the NMDAR antagonist (MK‐801). Fiber optic recordings reveal MK‐801 enhanced cue‐evoked neuronal responses in the olfactory bulb (OB), orbitofrontal cortex (OFC), ventral tegmental area (VTA), and nucleus accumbens (NAc), while reducing reward‐predictive cue selectivity and increasing NAc dopamine release. Additionally, in vivo electrophysiological recordings demonstrate that theta oscillation power in the NAc and its coherence with OB, OFC, and VTA are also amplified. MK‐801 treatment enhances the correlation between firing rates of NAc neurons and cue, decreases the association with reward, strengthens the correlation with licking and increases the probability of firing peak preceding lick onset. Furthermore, this work confirms that the application of the trace amine‐associated receptor 1 agonist SEP‐363856 could correct the abnormal responses of NAc neurons and behavioral deficits. These findings elucidate the neural basis of impulsivity and support the potential therapeutic effect of SEP.

Introduction Prenatal exposure to valproic acid (VPA) is a common environmental cause of autism spectrum disorder (ASD) and often leads to expressive and receptive language impairments. Similar communication difficulties among individuals with ASD are often linked to abnormal subcortical and cortical sound processing. Rodents prenatally exposed to VPA exhibit degraded cortical responses to speech and an impaired ability to behaviorally discriminate speech sounds. Methods We sought to determine whether sound processing could be restored with paired vagus nerve stimulation (VNS). In a first experiment, we evaluated whether sound-paired VNS would alter in vivo extracellular multi-unit responses to tones, noise burst trains, and speech sounds from the anterior auditory field. We next sought to evaluate whether improvements to neural sound processing led to improvements in sound discrimination ability. In a second experiment, rats underwent go/no-go sound discrimination testing where VNS was paired with successful trials. Results We found that VPA-exposed rats had degraded spectral, temporal, and speech sound processing compared to saline-exposed control rats. VPA-exposed rats which received sound-paired VNS exhibited a partial or full restoration of processing across sound types. However, across several sound discrimination tasks, we did not observe changes in behavioral performance in response to prenatal exposure to VPA or VNS. Discussion Our study is the first to show that speech-paired VNS leads to a generalized improvement in cortical sound processing across sound types, rescuing neural processing among VPA-exposed rats. These results provide a framework for future studies to develop VNS-based interventions for communication disorders.

In bats, which express a complex vocal repertoire and are considered vocal learners, the frontal auditory field (FAF) is supposedly placed in a frontal cortico‐striatal network for vocal–motor control. The FAF receives input from the auditory cortex (AC) and other auditory nuclei via multiple pathways. However, not much is known about the transition of information on vocalizations from the AC to the FAF. The bat AC consists of different subfields, among which the dorsal fields (dAC) are characterized by precise coding of the temporal envelope of vocalizations. The dAC should, therefore, be a major source of auditory feedback information about self‐produced or perceived vocalizations to the FAF. Our study aimed to investigate the specificity of encoding for different types of vocalizations in FAF and dAC neurons. Using extracellular recordings in anesthetized Phyllostomus discolor , we describe basic response properties in both cortical areas and compare responses to different types of prerecorded vocalizations. The specificity of encoding for different behaviorally relevant call categories and single calls was higher in dAC than in FAF neurons, both in terms of temporal firing patterns and response strength. These findings highlight the importance of the dAC in the neural network for control of vocal communication in bats.

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.

Tinnitus has been identified as a potential contributor to anxiety. Thalamo-cortical pathway plays a crucial role in the transmission of auditory and emotional information, but its casual link to tinnitus-associated anxiety remains unclear. In this study, we explore the neural activities in the thalamus and cortex of the sodium salicylate (NaSal)-treated mice, which exhibit both hyperacusis and anxiety-like behaviors. We find an increase in gamma band oscillations (GBO) in both auditory cortex (AC) and prefrontal cortex (PFC), as well as phase-locking between cortical GBO and thalamic neural activity. These changes are attributable to a suppression of GABAergic neuron activity in thalamic reticular nucleus (TRN), and optogenetic activation of TRN reduces NaSal-induced hyperacusis and anxiety-like behaviors. The elevation of endocannabinoid (eCB)/ cannabinoid receptor 1 (CB1R) transmission in TRN contributes to the NaSal-induced abnormalities. Our results highlight the regulative role of TRN in the auditory and limbic thalamic-cortical pathways.

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.

The auditory steady-state response (ASSR) is a cortical oscillation induced by trains of 40 Hz acoustic stimuli. While the ASSR has been widely used in clinic measurement, the underlying neural mechanism remains poorly understood. In this study, we investigated the contribution of different stages of auditory thalamocortical pathwaymedial geniculate body (MGB), thalamic reticular nucleus (TRN), and auditory cortex (AC)to the generation and regulation of 40 Hz ASSR in C57BL/6 mice of both sexes. We found that the neural response synchronizing to 40 Hz sound stimuli was most prominent in the GABAergic neurons in the granular layer of AC and the ventral division of MGB (MGBv), which were regulated by optogenetic manipulation of TRN neurons. Behavioral experiments confirmed that disrupting TRN activity has a detrimental effect on the ability of mice to discriminate 40 Hz sounds. These findings revealed a thalamocortical mechanism helpful to interpret the results of clinical ASSR examinations. Significance Statement Our study contributes to clarifying the thalamocortical mechanisms underlying the generation and regulation of the auditory steady-state response (ASSR), which is commonly used in both clinical and neuroscience research to assess the integrity of auditory function. Combining a series of electrophysiological and optogenetic experiments, we demonstrate that the generation of cortical ASSR is dependent on the lemniscal thalamocortical projections originating from the ventral division of medial geniculate body to the GABAergic interneurons in the granule layer of the auditory cortex. Furthermore, the thalamocortical process for ASSR is strictly regulated by the activity of thalamic reticular nucleus (TRN) neurons. Behavioral experiments confirmed that dysfunction of TRN would cause a disruption of mice's behavioral performance in the auditory discrimination task.

During visual search, it is important to reduce the interference of distracting objects in the scene. The neuronal responses elicited by the search target stimulus are typically enhanced. However, it is equally important to suppress the representations of distracting stimuli, especially if they are salient and capture attention. We trained monkeys to make an eye movement to a unique “pop-out” shape stimulus among an array of distracting stimuli. One of these distractors had a salient color that varied across trials and differed from the color of the other stimuli, causing it to also pop-out. The monkeys were able to select the pop-out shape target with high accuracy and actively avoided the pop-out color distractor. This behavioral pattern was reflected in the activity of neurons in area V4. Responses to the shape targets were enhanced, while the activity evoked by the pop-out color distractor was only briefly enhanced, directly followed by a sustained period of pronounced suppression. These behavioral and neuronal results demonstrate a cortical selection mechanism that rapidly inverts a pop-out signal to “pop-in” for an entire feature dimension thereby facilitating goal-directed visual search in the presence of salient distractors.

Intracellular aggregation of hyperphosphorylated Tau (pTau) in the brain is associated with cognitive and motor impairments, and ultimately neurodegeneration. We investigate how human pTau affects cells and network activity in the hippocampal formation of the THY-Tau22 tauopathy model mice in vivo. We find that pTau preferentially accumulates in deep-layer pyramidal neurons, leading to neurodegeneration, and we establish that pTau spreads to oligodendrocytes. During goal-directed virtual navigation in aged transgenic mice, we detect fewer high-firing prosubicular pyramidal cells, but the firing population retains its coupling to theta oscillations. Analysis of network oscillations and firing patterns of pyramidal and GABAergic neurons recorded in head-fixed and freely moving mice suggests preserved neuronal coordination. In spatial memory tests, transgenic mice have reduced short-term familiarity, but spatial working and reference memory are surprisingly normal. We hypothesize that unimpaired subcortical network mechanisms maintain cortical neuronal coordination, counteracting the widespread pTau aggregation, loss of high-firing cells, and neurodegeneration.

Tinnitus is the phantom perception of sound that has no external source. A neurological signature of tinnitus, and the frequently associated hyperacusis, is an imbalance between excitatory and inhibitory activity in the central auditory system (CAS), leading to dysregulated network excitability. The large conductance, calcium-activated potassium (BK) channel is a key player in pre- and post-synaptic excitability through its mediation of K + currents. Changes in BK channel activity are associated with aberrant network activity in sensory regions of the CNS, raising the possibility that BK channel modulation could regulate activity associated with tinnitus and hyperacusis. To test whether BK channel openers are able to suppress biomarkers of drug-induced tinnitus and hyperacusis, the 1,3,4 oxadiazole BMS-191011 was given to young adult CBA mice that had been administered 250 mg/kg sodium salicylate (SS). Systemic treatment with BMS-191011 reduced behavioral manifestations of SS-induced tinnitus, but not hyperacusis, probed via the gap-in-noise startle response method. Systemic BMS-191011 treatment did not influence SS-induced increases in auditory brainstem response functions, but local application at the inferior colliculus did reverse SS-suppressed spontaneous activity, particularly in the frequency region of the tinnitus percept. Thus, action of BMS-191011 in the inferior colliculus may contribute to the reduction in behaviorally measured tinnitus. Together, these findings support the utility of BK channel openers in reducing central auditory processing changes associated with the formation of the tinnitus percept.

Dominant neuroanatomical models hold that humans regulate their movements via loop-like cortico-subcortical networks, which include the subthalamic nucleus (STN), motor thalamus, and sensorimotor cortex (SMC). Inhibitory commands across these networks are purportedly sent via transient, burst-like signals in the β frequency (15–29 Hz). However, since human depth-recording studies are typically limited to one recording site, direct evidence for this proposition is hitherto lacking. Here, we present simultaneous multi-site recordings from SMC and either STN or motor thalamus in humans performing the stop-signal task. In line with their purported function as inhibitory signals, subcortical β-bursts were increased on successful stop-trials. STN bursts in particular were followed within 50 ms by increased β-bursting over SMC. Moreover, between-site comparisons (including in a patient with simultaneous recordings from SMC, thalamus, and STN) confirmed that β-bursts in STN temporally precede thalamic β-bursts. This highly unique set of recordings provides empirical evidence for the role of β-bursts in conveying inhibitory commands along long-proposed cortico-subcortical networks underlying movement regulation in humans.

During vocal communication, the spectro-temporal structure of vocalizations conveys important contextual information. Bats excel in the use of sounds for echolocation by meticulous encoding of signals in the temporal domain. We therefore hypothesized that for social communication as well, bats would excel at detecting minute distortions in the spectro-temporal structure of calls. To test this hypothesis, we systematically introduced spectro-temporal distortion to communication calls of Phyllostomus discolor bats. We broke down each call into windows of the same length and randomized the phase spectrum inside each window. The overall degree of spectro-temporal distortion in communication calls increased with window length. Modelling the bat auditory periphery revealed that cochlear mechanisms allow discrimination of fast spectro-temporal envelopes. We evaluated model predictions with experimental psychophysical and neurophysiological data. We first assessed bats’ performance in discriminating original versions of calls from increasingly distorted versions of the same calls. We further examined cortical responses to determine additional specializations for call discrimination at the cortical level. Psychophysical and cortical responses concurred with model predictions, revealing discrimination thresholds in the range of 8–15 ms randomization-window length. Our data suggest that specialized cortical areas are not necessary to impart psychophysical resilience to temporal distortion in communication calls.

The temporal frequency of sensory stimulation is a decisive factor in the plasticity of perceptual detection thresholds. However, surprisingly little is known about how distinct temporal parameters of sensory input differentially recruit activity of neuronal circuits in sensory cortices. Here we demonstrate that brief repetitive visual stimulation induces long-term plasticity of visual responses revealed 24 h after stimulation and that the location and generalization of visual response plasticity is determined by the temporal frequency of the visual stimulation. Brief repetitive low-frequency stimulation (2 Hz) is sufficient to induce a visual response potentiation that is expressed exclusively in visual cortex layer 4 and in response to a familiar stimulus. In contrast, brief, repetitive high-frequency stimulation (HFS, 20 Hz) is sufficient to induce a visual response potentiation that is expressed in all cortical layers and transfers to novel stimuli. HFS induces a long-term suppression of the activity of fast-spiking interneurons and primes ongoing gamma oscillatory rhythms for phase reset by subsequent visual stimulation. This novel form of generalized visual response enhancement induced by HFS is paralleled by an increase in visual acuity, measured as improved performance in a visual detection task.

Many tasks demand that information is kept online for a few seconds before it is used to guide behavior. The information is kept in working memory as the persistent firing of neurons encoding the memorized information. The neural mechanisms responsible for persistent activity are not yet well understood. Theories attribute an important role to ionotropic glutamate receptors, and it has been suggested that NMDARs are particularly important for persistent firing because they exhibit long time constants. Ionotropic AMPARs have shorter time constants and have been suggested to play a smaller role in working memory. Here we compared the contribution of AMPARs and NMDARs to persistent firing in the dlPFC of male macaque monkeys performing a delayed saccade to a memorized spatial location. We used iontophoresis to eject small amounts of glutamate receptor antagonists, aiming to perturb, but not abolish, neuronal activity. We found that both AMPARs and NMDARs contributed to persistent activity. Blockers of the NMDARs decreased persistent firing associated with the memory of the neuron's preferred spatial location but had comparatively little effect on the representation of the antipreferred location. They therefore decreased the information conveyed by persistent firing about the memorized location. In contrast, AMPAR blockers decreased activity elicited by the memory of both the preferred and antipreferred location, with a smaller effect on the information conveyed by persistent activity. Our results provide new insights into the contribution of AMPARs and NMDARs to persistent activity during working memory tasks. SIGNIFICANCE STATEMENT Working memory enables us to hold on to information that is no longer available to the senses. It relies on the persistent activity of neurons that code for the memorized information, but the detailed mechanisms are not yet well understood. Here we investigated the role of NMDARs and AMPARs in working memory using iontophoresis of antagonists in the PFC of monkeys remembering the location of a visual stimulus for an eye movement response. AMPARs and NMDARs both contributed to persistent activity. NMDAR blockers mostly decreased persistent firing associated with the memory of the neuron's preferred spatial location, whereas AMPAR blockers caused a more general suppression. These results provide new insight into the contribution of AMPARs and NMDARs to working memory.

The medial septum implements cortical theta oscillations, a 5-12 Hz rhythm associated with locomotion and paradoxical sleep reflecting synchronization of neuronal assemblies such as place cell sequence coding. Highly rhythmic burst-firing parvalbumin-positive GABAergic medial septal neurons are strongly coupled to theta oscillations and target cortical GABAergic interneurons, contributing to coordination within one or several cortical regions. However, a large population of medial septal neurons of unidentified neurotransmitter phenotype and with unknown axonal target areas fire with a low degree of rhythmicity. We investigated whether low-rhythmic-firing neurons (LRNs) innervated similar or different cortical regions to high-rhythmic-firing neurons (HRNs) and assessed their temporal dynamics in awake male mice. The majority of LRNs were GABAergic and parvalbumin-immunonegative, some expressing calbindin; they innervated interneurons mostly in the dentate gyrus (DG) and CA3. Individual LRNs showed several distinct firing patterns during immobility and locomotion, forming a parallel inhibitory stream for the modulation of cortical interneurons. Despite their fluctuating firing rates, the preferred firing phase of LRNs during theta oscillations matched the highest firing probability phase of principal cells in the DG and CA3. In addition, as a population, LRNs were markedly suppressed during hippocampal sharp-wave ripples, had a low burst incidence, and several of them did not fire on all theta cycles. Therefore, CA3 receives GABAergic input from both HRNs and LRNs, but the DG receives mainly LRN input. We propose that distinct GABAergic LRNs contribute to changing the excitability of the DG and CA3 during memory discrimination via transient disinhibition of principal cells.SIGNIFICANCE STATEMENT For the encoding and recall of episodic memories, nerve cells in the cerebral cortex are activated in precisely timed sequences. Rhythmicity facilitates the coordination of neuronal activity and these rhythms are detected as oscillations of different frequencies such as 5-12 Hz theta oscillations. Degradation of these rhythms, such as through neurodegeneration, causes memory deficits. The medial septum, a part of the basal forebrain that innervates the hippocampal formation, contains high- and low-rhythmic-firing neurons (HRNs and LRNs, respectively), which may contribute differentially to cortical neuronal coordination. We discovered that GABAergic LRNs preferentially innervate the dentate gyrus and the CA3 area of the hippocampus, regions important for episodic memory. These neurons act in parallel with the HRNs mostly via transient inhibition of inhibitory neurons.

Active mechanical amplification of sound occurs in cochlear outer hair cells (OHCs) that change their length with oscillations of their membrane potential. Such length changes are the proposed cellular source of the cochlear amplifier, and prestin is the motor protein responsible for OHC electromotility. Previous findings have shown that mice lacking prestin displayed a loss of OHC electromotility, subsequent loss of distortion-product otoacoustic emissions, and a 40-60 dB increase in hearing thresholds. In this study we were interested in studying the functional consequences of the complete loss of cochlear amplification on neural coding of frequency selectivity, tuning, and temporal processing in the auditory midbrain. We recorded near-field auditory evoked potentials and multi-unit activity from the inferior colliculus (IC) of prestin (-/-) null and prestin (+/+) wild-type control mice and determined frequency response areas (FRAs), tuning sharpness, and gap detection to tone bursts and silent gaps embedded in broadband noise. We were interested in determining if the moderate to severe sensorineural hearing loss associated with the loss of motor protein prestin would also impair auditory midbrain temporal-processing measures, or if compensatory mechanisms within the brainstem could compensate for the loss of prestin. In prestin knockout mice we observed that there are severe impairments in midbrain tuning, thresholds, excitatory drive, and gap detection suggesting that brainstem and midbrain processing could not overcome the auditory processing deficits afforded by the loss of OHC electromotility mediated by the prestin protein.

Introduction It is known that an interruption of acoustic input in early life will result in abnormal development of the auditory system. Here, we further show that this negative impact actually spans beyond the auditory system to the hippocampus, a system critical for spatial memory. Methods We induced a temporary conductive hearing loss (TCHL) in P14 rats by perforating the eardrum and allowing it to heal. The Morris water maze and Y‐maze tests were deployed to evaluate spatial memory of the rats. Electrophysiological recordings and anatomical analysis were made to evaluate functional and structural changes in the hippocampus following TCHL. Results The rats with the TCHL had nearly normal hearing at P42, but had a decreased performance with the Morris water maze and Y‐maze tests compared with the control group. A functional deficit in the hippocampus of the rats with the TCHL was found as revealed by the depressed long‐term potentiation and the reduced NMDA receptor‐mediated postsynaptic current. A structural deficit in the hippocampus of those animals was also found as revealed the abnormal expression of the NMDA receptors, the decreased number of dendritic spines, the reduced postsynaptic density and the reduced level of neurogenesis. Conclusions Our study demonstrates that even temporary auditory sensory deprivation in early life of rats results in abnormal development of the hippocampus and consequently impairs spatial memory in adulthood.