Behavioral Neuroscience publications

Neural dynamics are thought to reflect computations that relay and transform information in the brain. Previous studies have identified the neural population dynamics in many individual brain regions as a trajectory geometry, preserving a common computational motif. However, whether these populations share particular geometric patterns across brain-wide neural populations remains unclear. Here, by mapping neural dynamics widely across temporal/frontal/limbic regions in the cortical and subcortical structures of monkeys, we show that 10 neural populations, including 2,500 neurons, propagate visual item information in a stochastic manner. We found that visual inputs predominantly evoked rotational dynamics in the higher-order visual area, TE, and its downstream striatum tail, while curvy/straight dynamics appeared frequently downstream in the orbitofrontal/hippocampal network. These geometric changes were not deterministic but rather stochastic according to their respective emergence rates. Our meta-analysis results indicate that visual information propagates as a heterogeneous mixture of stochastic neural population signals in the brain.

Face processing models propose gradually more complex receptive field properties culminating in invariant representations in anterior inferotemporal cortex (aITC), leading to late socio-emotionally relevant encoding in pre- and orbitofrontal cortex (POC). Top-down facilitation models, however, predict that some lower-level POC neurons respond faster than aITC. To resolve this discrepancy, we recorded from 2,459 neurons in fMRI-defined POC and aITC face patches. POC patches are more heterogeneous, containing smaller fractions of face-selective neurons than aITC and a mixture of responses to faces and non-faces. In one POC patch, face responses are surprisingly fast, outpacing those in aITC. Moreover, its responses correlate inversely with stimulus spatial frequency. Hence, our extensive data, with a large diversity of POC neurons, support both models and suggest one POC face patch might be specialized in fast, low-level face processing, which may enable (partially) invariant face representations during subsequent processing stages in inferotemporal cortex (ITC).

Recent studies show that systemic administration of a glucagon-like peptide-1 receptor (GLP-1R) agonist is sufficient to attenuate cocaine seeking. However, the neural mechanisms mediating these effects and the role of endogenous central GLP-1 signaling in cocaine seeking remain unknown. Here, we show that voluntary cocaine taking decreased plasma GLP-1 levels in rats and that chemogenetic activation of GLP-1–producing neurons in the nucleus tractus solitarius that project to the ventral tegmental area (VTA) decreased cocaine seeking. Single-nuclei transcriptomics and FISH studies revealed that GLP-1Rs are expressed primarily on GABA neurons in the VTA. Using in vivo fiber photometry, we found that the efficacy of a systemic GLP-1R agonist to attenuate cocaine seeking was associated with increased activity of VTA GABA neurons and decreased activity of VTA dopamine neurons. Together, these findings suggest that targeting central GLP-1 circuits may be an effective strategy toward reducing cocaine relapse and highlight a functional role of GABAergic GLP-1R–expressing midbrain neurons in drug seeking.

Episodic memory relies on the formation and retrieval of content-specific memory traces. In addition to their veridical reactivation, previous studies have indicated that traces may undergo substantial transformations. However, the exact time course and regional distribution of reinstatement and transformation during recognition memory have remained unclear. We applied representational similarity analysis to human intracranial electroencephalography to track the spatiotemporal dynamics underlying the reinstatement and transformation of memory traces. Specifically, we examined how reinstatement and transformation of item-specific representations across occipital, ventral visual, and lateral parietal cortices contribute to successful memory formation and recognition. Our findings suggest that reinstatement in temporal cortex and transformation in parietal cortex coexist and provide complementary strategies for recognition. Further, we find that generalization and differentiation of neural representations contribute to memory and probe memory-specific correspondence with deep neural network (DNN) model features. Our results suggest that memory formation is particularly supported by generalized and mnemonic representational formats beyond the visual features of a DNN.

The medial prefrontal cortex (mPFC) is critical for learning and decision-making processes, including responding to threats. The protracted maturation of the mPFC extends into early adulthood. Although prominent models suggest that increasing top-down control by the mPFC eventually allows adult behavioral repertoires to emerge, it is unclear how progressive strengthening can produce nonlinear behavioral changes observed across development. We use fiber photometry and optogenetics to establish causal links between frontolimbic pathway activity and threat avoidance strategies in juvenile, adolescent and adult mice. We uncover multiple developmental switches in the roles of mPFC pathways targeting the nucleus accumbens and basolateral amygdala. These changes are accompanied by axonal pruning, strengthening of synaptic connectivity and altered functional connectivity with downstream cell types, which occur in the mPFC-basolateral amygdala and mPFC-nucleus accumbens pathways at different rates. Our results reveal how developing mPFC pathways pass through distinct architectures that may make them optimally adapted to age-specific challenges.

Auditory neuropathies affect the spiral ganglion neurons of the auditory nerve or their synapses with the sensory hair cells, distorting the sound information transmitted from the ear to the brain. Deciphering the underlying pathophysiological mechanisms remains challenging owing to the diversity of spiral ganglion neuron subtypes and associated central auditory circuits. An auditory neuropathy mechanism is unraveled by investigating the origin of auditory hyperexcitability in a mouse model for hereditary congenital deafness. Otogl encodes the large Otogelin‐like protein, which is related to secreted epithelial mucins and is implicated in the mechanical stimulation of cochlear outer hair cells. Heterozygous Otogl +/− mutant mice display auditory hyperexcitability, highlighted by their susceptibility to audiogenic seizures induced by loud sounds. It is shown that Otogl is transiently expressed in a subpopulation of spiral ganglion neurons during cochlear development. Despite their apparently normal hearing, Otogl +/− mice display poor activation of the spiral ganglion neurons processing loud sounds and an elevation of the activation threshold of the middle the ear muscle reflex that attenuates loud sounds. The findings reveal how a neuropathy affecting spiral ganglion neurons specialized in loud sound processing and associated with the middle the ear muscle reflex can manifest itself as auditory hyperexcitability.

Value-based decision–making involves multiple cortical and subcortical brain areas, but the distributed nature of neurophysiological activity underlying economic choices in the human brain remains largely unexplored. Specifically, the nature of the neurophysiological representation of reward-guided choices, as well as whether they are represented in a subset of reward-related regions or in a more distributed fashion, is unknown. Here, we hypothesize that reward choices, as well as choice-related computations (win probability, risk), are primarily represented in high-frequency neural activity reflecting local cortical processing and that they are highly distributed throughout the human brain, engaging multiple brain regions. To test these hypotheses, we used intracranial recordings from multiple areas (including orbitofrontal, lateral prefrontal, parietal, cingulate cortices as well as subcortical regions such as the hippocampus and amygdala) from neurosurgical patients of both sexes playing a decision-making game. We show that high-frequency activity (HFA; ɣ and HFA) represents both individual choice-related computations (e.g., risk, win probability) and choice information with different prevalence and regional representation. Choice-related computations are locally and unevenly present in multiple brain regions, whereas choice information is widely distributed and more prevalent and appears later across all regions examined. These results suggest brain-wide reward processing, with local HFA reflecting the coalescence of choice-related information into a final choice, and shed light on the distributed nature of neural activity underlying economic choices in the human brain.

The striatum is the primary input nucleus of the basal ganglia, integrating a dense plexus of inputs from the cerebral cortex and thalamus to regulate action selection and learning. Neuroanatomical mapping of the striatum and its subcompartments has been carried out extensively in rats and mice, nonhuman primates, and cats allowing comparative neuroanatomy studies to derive heuristics about striatal composition and function. Here, we systematically map corticostriatal topography from motor, somatosensory, auditory, and visual cortices as well as thalamostriatal parafascicular (PfN) inputs in the Mongolian gerbil. We also map a pathway reported in mice from medial vestibular nucleus to the PfN that could convey vestibular information to the striatum. Our findings align with those of similar studies in other rodents, indicating homologous neuroanatomical connectivity patterns within the corticostriatal projectome across Rodentia. We observed corticostriatal peaks of dense labeling for each input with a diffuse projection throughout striatal subregions from each cortical region, suggesting a global integration of all cortical information by the striatum. Thalamostriatal projections from PfN covered most of the striatum with a peak of PfN-specific compartmentalized labeling similar to other sensory and motor systems. We also confirm the connection from the medial vestibular nucleus to PfN thalamus, indicating that vestibular information may be widely integrated throughout the striatum. The findings build upon our body of knowledge on striatal connectivity across mammalian species and provide a foundation for striatal research focusing on vestibulothalamostriatal circuits in Rodentia.

Mammillary body (MB) is traditionally viewed as a structural node of an anatomic circuit for emotion and memory. However, little is known about its molecular and cellular organizations. Here, a discovery that MB contains four subtypes of neurons that occupy different spatial subregions is reported. Of these, two subtypes of neurons are tagged by parvalbumin (PV) and dopamine receptor‐D2 (Drd2) markers. PV neurons are spontaneously active, whereas Drd2 neurons are inactive at rest and generate rebound bursts. These two distinct electrophysiological properties are encoded by Kcnn4 and Cacna1h . PV and Drd2 neurons generate two distinct cell‐type specific circuits by receiving inputs from two discrete subiculum neuronal classes. Gain‐ and loss‐of‐function studies on these cortical‐subcortical circuits demonstrate their differential roles for place and object recognition memory. This finding provides a comprehensive molecular and structural atlas of MB neurons at single‐cell resolution and reveals that MB contains molecularly, structurally, and functionally dissociable streams within its serial architecture.

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic nigrostriatal inputs, which causes striatal network dysfunction and leads to pronounced motor deficits. Recent evidence highlights astrocytes as a potential local source for striatal neuromodulation. There is substantial evidence for norepinephrine‐mediated recruitment of cortical astrocyte activity during movement and locomotion. However, it is unclear how astrocytes in the striatum, a region devoid of norepinephrine neuromodulatory inputs, respond during locomotion. Moreover, it remains unknown how dopamine loss affects striatal astrocyte activity and whether astrocyte activity regulates behavioral deficits in PD. We addressed these questions by performing astrocyte‐specific calcium recordings and manipulations using in vivo fiber photometry and chemogenetics. We find that locomotion elicits astrocyte calcium activity over a slower timescale than neurons. Acute pharmacological blockade of dopamine receptors only moderately reduced locomotion‐related astrocyte activity. Yet, unilateral dopamine depletion significantly attenuated astrocyte calcium responses. Chemogenetic stimulation of G i ‐coupled receptors partially improved this functional astrocyte deficit in dopamine‐lesioned mice. In parallel, chemogenetic manipulation restored asymmetrical motor deficits and moderately improved open‐field exploratory behavior. Together, our results establish a novel role for functional striatal astrocyte signaling in modulating motor function in PD and highlight non‐neuronal targets for potential PD therapeutics.

Noise-induced cochlear synaptopathy has been studied for over 25 years with no known diagnosis for this disorder in humans. This type of "hidden hearing loss" induces a loss of synapses in the inner ear but no change in audiometric thresholds. Recent studies have shown that by two months post synaptopathy-inducing noise exposure, synapses in some animal species can regenerate. Animal studies to date have focused primarily on peripheral hearing measures to diagnose ribbon synapse loss, while suggesting binaural listening deficits such as speech-reception-in-noise result from this disorder, but haven't accounted for the possible regeneration of synapses. To address this, we measured binaural physiological and behavioral function, the latter utilizing the pre-pulse inhibition of acoustic startle method, in both male and female adult guinea pigs following exposure to noise that has been shown to induce cochlear synaptopathy. Physiological measurements extended to 2 months post noise exposure to characterize any deficit and subsequent recovery. While common audiological assessments showed temporary threshold shift, reduced evoked potential amplitudes indicative of synaptopathy and measurable binaural electrophysiological hearing deficits post exposure, all measures recovered by 2 months. Suspected regeneration of synaptic ribbons occurred by 2 months post exposure and cochlear histology revealed no synaptic loss 4 months post exposure. Our results show that the same noise exposure protocol demonstrated to cause synaptic loss in prior studies causes physiological binaural processing deficits in the brainstem and that the recovery of neural binaural processing coincides with the regeneration of synapses shown in previous studies and normal binaural hearing behavior.

Multiple studies suggest that Parkinson's disease (PD) is associated with changes in neuronal activity throughout the basal ganglia-thalamocortical motor circuit. There are limited electrophysiological data, however, describing how parkinsonism impacts neuronal activity in the presupplementary motor area (pre-SMA), an area in the medial frontal cortex involved in movement planning and motor control. In this study, single unit activity was recorded in the pre-SMA of two female nonhuman primates during a visually cued reaching task in both the naive and parkinsonian state using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of parkinsonism. In the naive state, neuronal discharge rates were dynamically modulated prior to the presentation of the instructional go-cue. In a subset of these modulated cells, the magnitude of modulation correlated linearly with reaction time (RT). In the parkinsonian state, however, modulation of discharge rates in the pre-SMA was disrupted, and the predictive encoding of RT was significantly diminished. These findings add to our understanding of the role of pre-SMA in motor behavior and suggest that disrupted encoding in this cortical region contributes to the alteration of early preparatory and premovement processes present in Parkinson's disease.

The inferior colliculus (IC) has traditionally been regarded as an important relay in the auditory pathway, primarily involved in relaying auditory information from the brainstem to the thalamus. However, this study uncovers the multifaceted role of the IC in bridging auditory processing, sensory prediction, and reward prediction. Through extracellular recordings in monkeys engaged in a sound duration-based deviation detection task, we observed a 'climbing effect' in neuronal firing rates, indicative of an enhanced response over sound sequences linked to sensory prediction rather than reward anticipation. Moreover, our findings demonstrate reward prediction errors within the IC, highlighting its complex integration in auditory and reward processing. Further analysis revealed a direct correlation between IC neuronal activity and behavioral choices, suggesting its involvement in decision-making processes. This research highlights a more complex role for the IC than traditionally understood, showcasing its integral role in cognitive and sensory processing and emphasizing its importance in integrated brain functions.

Introduction Perceived loudness is challenging to study in non-human animals. However, reaction time to an acoustic stimulus is a useful behavioral proxy for the assessment of perceived loudness. Understanding the effect of sound frequency and level on perceived loudness would improve prediction and modeling of anthropogenic noise impacts on marine mammals. Methods In this study, behavioral hearing tests conducted with two killer whales were analyzed to capture conditioned vocal response latency, which is the time between the onset of the acoustic signal and the onset of the response (i.e., reaction time). Results The results showed that vocal reaction times decreased with increasing sensation level (i.e., sound pressure level above the baseline hearing threshold), while the effect of frequency on reaction time varied between the subjects. Reaction time as a function of sound duration is described, and equal-latency contours are presented. Discussion The data suggest that vocal reaction time decreases with increasing sensation level, therefore supporting the use of reaction time as a proxy for loudness perception in killer whales.

Background Parkinson’s disease (PD) is often characterized by altered rates and patterns of neuronal activity in the sensorimotor regions of the basal ganglia thalamocortical network. Little is known, however, regarding how neuronal activity in the executive control network of the brain changes in the parkinsonian condition. Objective Investigate the impact of parkinsonism on neuronal activity in the dorsolateral prefrontal cortex (DLPFC), a key region in executive control, during a go/nogo reaching task. Methods Using a within-subject design, single and multi-unit neuronal activity was recorded in the DLPFC of a nonhuman primate ( n = 1) before and after the induction of mild parkinsonism using the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Results Coincident with development of mild parkinsonian motor signs, there was a marked reduction in the percentage of DLPFC cells with significant task-related firing rate modulation during go and nogo conditions. Conclusion These results suggest that DLPFC dysfunction may occur early in parkinsonism and contribute to cognitive impairments and disrupted executive function often observed in PD patients.

The manner in which neural activity unfolds over time is thought to be central to sensory, motor and cognitive functions in the brain. Network models have long posited that the brain's computations involve time courses of activity that are shaped by the underlying network. A prediction from this view is that the activity time courses should be difficult to violate. We leveraged a brain-computer interface to challenge monkeys to violate the naturally occurring time courses of neural population activity that we observed in the motor cortex. This included challenging animals to traverse the natural time course of neural activity in a time-reversed manner. Animals were unable to violate the natural time courses of neural activity when directly challenged to do so. These results provide empirical support for the view that activity time courses observed in the brain indeed reflect the underlying network-level computational mechanisms that they are believed to implement.

Loud noise exposure is one of the leading causes of permanent hearing loss. Individuals with noise-induced hearing loss (NIHL) suffer from speech comprehension deficits and experience impairments to cognitive functions such as attention and decision-making. Here, we investigate the specific underlying cognitive processes during auditory perceptual decision-making that are impacted by NIHL. Gerbils were trained to perform an auditory decision-making task that involves discriminating between slow and fast presentation rates of amplitude-modulated (AM) noise. Decision-making task performance was assessed across pre- versus post-NIHL sessions within the same gerbils. A single exposure session (2 h) to loud broadband noise (120 dB SPL) produced permanent NIHL with elevated threshold shifts in auditory brainstem responses (ABRs). Following NIHL, decision-making task performance was tested at sensation levels comparable to those prior to noise exposure in all animals. Our findings demonstrate NIHL diminished perceptual acuity, reduced attentional focus, altered choice bias, and slowed down evidence accumulation speed. Finally, video-tracking analysis of motor behavior during task performance demonstrates that NIHL can impact sensory-guided decision-based motor execution. Together, these results suggest that NIHL impairs the sensory, cognitive, and motor factors that support auditory decision-making.

High-frequency stimulation (HFS)-induced long–term potentiation (LTP) is generally regarded as a homosynaptic Hebbian-type LTP, where synaptic changes are thought to occur at the synapses that project from the stimulation site and terminate onto the neurons at the recording site. In this study, we first investigated HFS-induced LTP on urethane-anesthetized rats and found that cortical HFS enhances neural responses at the recording site through the strengthening of local connectivity with nearby neurons at the stimulation site rather than through synaptic strengthening at the recording site. This enhanced local connectivity at the stimulation site leads to increased output propagation, resulting in signal potentiation at the recording site. Additionally, we discovered that HFS can also nonspecifically strengthen distant afferent synapses at the HFS site, thereby expanding its impact beyond local neural connections. This form of plasticity exhibits a neo-Hebbian characteristic as it exclusively manifests in the presence of cholecystokinin release, induced by HFS. The cortical HFS-induced local LTP was further supported by a behavioral task, providing additional evidence. Our results unveil a previously overlooked mechanism underlying cortical plasticity: synaptic plasticity is more likely to occur around the soma site of strongly activated cortical neurons rather than solely at their projection terminals.

Tinnitus, a widespread condition affecting numerous individuals worldwide, remains a significant challenge due to limited effective therapeutic interventions. Intriguingly, patients using cochlear implants (CIs) have reported significant relief from tinnitus symptoms, although the underlying mechanisms remain unclear and intracochlear implantation risks cochlear damage and hearing loss. This study demonstrates that targeted intracochlear electrical stimulation (ES) in guinea pigs with noise‐induced hearing loss reversed tinnitus‐related maladaptive plasticity in the cochlear nucleus (CN), characterized by reduced auditory innervation, increased somatosensory innervation, and diminished inhibitory neural networks. Additionally, a customized extracochlear ES delivered by a newly designed extracochlear electrode array to guinea pigs with salicylate‐induced tinnitus also reversed the aforementioned maladaptive plasticity and alleviated tinnitus without causing additional cochlear damage or hearing loss. These findings suggest that CI‐delivered ES may alleviate tinnitus by reversing maladaptive CN plasticity. Additionally, the extracochlear ES strategy offers a promising tinnitus treatment with minimal risk to hearing.

Recognition of vocal identity is essential for primate social behavior, yet the neural mechanisms supporting this ability remain poorly understood. Cognitive models suggest that the brain may represent identity based on an average voice prototype. Here, we tested this hypothesis by recording spiking activity from single neurons in an fMRI-localized voice-selective region of the anterior temporal lobe in two rhesus macaques. Using synthetic “coo” calls systematically morphed along identity trajectories from “anti-voices” to caricatures, we found that early neuronal responses (∼100 ms post-stimulus) exhibited robust V-shaped tuning to distance from the average voice. This pattern reflects an energy-efficient representational strategy in which neural activity increases with identity distinctiveness, also applied to face stimuli. Unexpectedly, a distinct subpopulation of neurons showed a delayed (∼200 ms) rebound response selectively enhanced for the average voice. These findings reveal two temporally dissociable mechanisms for vocal identity encoding in primate auditory cortex, suggesting that the brain emphasizes both distinctiveness and prototypicality to support efficient and flexible voice recognition. Significance statement Recognizing who is speaking is fundamental to primate social life, yet how the brain encodes vocal identity remains poorly understood. Cognitive theories suggest that the brain may represent identity relative to an internal “average” voice, but direct neural evidence has been lacking. Here, we recorded single-neuron activity in a voice-selective brain region of rhesus macaques and found two distinct coding strategies: one that increases neural activity with identity distinctiveness, and another that selectively enhances the average voice itself. These results reveal dual mechanisms for vocal identity encoding in the primate brain, highlighting how the brain balances flexibility and efficiency in social communication.