Single Unit publications

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.

Objective. In the present study, we examined the correlations between the recovery of stepping obtained with intrathecal brain derived neurotrophic factor (BDNF) delivery to the lumbar spinal cord and the firing of the lumbar spinal interneurons in a feline model of spinal cord injury (SCI). Approach. In-vivo extracellular recordings of spinal neurons were conducted using two 64-channel microelectrode arrays inserted in the intermediate zone of the L3–L7 segments of cats spinalized at the T11–T12 level that received either saline or BDNF delivered intrathecally to the lumbar cisterna via an implanted minipump. Interneuronal activity was explored in terms of averaged neuronal firing properties and in terms of spike train interactions. Main results. With respect to averaged neuronal firing properties, we observed a significant increase in firing frequency in BNDF-treated animals and a similar distribution of the units’ preferred phase of firing relative to the step cycle between the groups. With respect to spike train interactions, we observed higher synchrony of firing in BDNF-treated animals as well as less dependency on the unit’s past firing. Significance. Studies conducted in feline models of complete SCI show a gradual recovery of hindlimb stepping after intensive treadmill training. Similarly, delivery of neurotrophins such as BDNF or neurotrophin-3 to the injury site via cellular transplant or via implantable mini-pump to the lumbar cisterna has been shown to promote recovery of locomotor behavior in the absence of locomotor training. The results from this study suggest that BDNF treatment sets the overall population in a state of high excitability, which along with higher synchrony and ensemble-dependent behavior, allows for the proper integration of cutaneous and proprioceptive input resulting in treadmill locomotor recovery after SCI.

The macaque cerebral cortex contains concentrations of neurons that prefer faces over inanimate objects. Although these so-called face patches are thought to be specialized for the analysis of facial signals, their exact tuning properties remain unclear. For example, what happens when an object by chance resembles a face? Everyday objects can sometimes, through the accidental positioning of their internal components, appear as faces. This phenomenon is known as face pareidolia. Behavioral experiments have suggested that macaques, like humans, perceive illusory faces in such objects. However, it is an open question whether such stimuli would naturally stimulate neurons residing in cortical face patches. To address this question, we recorded single unit activity from four fMRI-defined face-selective regions: the anterior medial (AM), anterior fundus (AF), prefrontal orbital (PO), and perirhinal cortex (PRh) face patches. We compared neural responses elicited by images of real macaque faces, pareidolia-evoking objects, and matched control objects. Contrary to expectations, we found no evidence of a general preference for pareidolia-evoking objects over control objects. Although a subset of neurons exhibited stronger responses to pareidolia-evoking objects, the population responses to both categories of objects were similar, and collectively much less than to real macaque faces. These results suggest that neural responses in the four regions we tested are principally concerned with the analysis of realistic facial characteristics, whereas the special attention afforded to face-like pareidolia stimuli is supported by activity elsewhere in the brain.

The neural basis of perceptual distortions induced by psychedelics remains poorly understood. This study demonstrates that the serotonergic psychedelic DOI increases neural response variability and impairs deviance detection in the auditory cortex by reducing sensitivity to unexpected sounds. These findings provide new insights into how psychedelics disrupt sensory processing and alter the balance between bottom-up and top-down neural signaling, contributing to our understanding of altered perception in the psychedelic state.

Cricket song recognition is thought to evolve through modifications of a shared neural network. However, the species Anurogryllus muticus has an unusual recognition pattern that challenges this view: females respond to both normal male song pulse periods and periods twice as long. Of the three minimal models tested, only a single-neuron model with an oscillating membrane could explain this unusual behavior. A minimal model of the cricket's song network reproduced the behavior after adding a mechanism that, while present in the full network, is not crucial for song recognition in other species. This shows how a shared neural network can produce diverse behaviors and highlights how different computations contribute to evolution. Our results also demonstrate how nonlinear computations can lead to rapid behavioral changes during evolution because small changes in network parameters can lead to large changes in 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 structure of local circuits is highly conserved across the cortex, yet the spatial and temporal properties of population activity differ fundamentally in sensory-level and association-level areas. In the sensory cortex, population activity has a shorter timescale and decays sharply over distance, supporting a population code for the fine-scale features of sensory stimuli. In the association cortex, population activity has a longer timescale and spreads over wider distances, a code that is suited to holding information in memory and driving behavior. We tested whether these differences in activity dynamics could be explained by differences in network structure. We targeted photostimulations to single excitatory neurons of layer 2/3, while monitoring surrounding population activity using two-photon calcium imaging. Experiments were performed in the auditory (AC) and posterior parietal cortex (PPC) within the same mice of both sexes, which also expressed a red fluorophore in somatostatin-expressing interneurons (SOM). In both cortical regions, photostimulations resulted in a spatially restricted zone of positive influence on neurons closely neighboring the targeted neuron and a more spatially diffuse zone of negative influence affecting more distant neurons (akin to a network-level “suppressive surround”). However, the relative spatial extents of positive and negative influence were different in AC and PPC. In PPC, the central zone of positive influence was wider, but the negative suppressive surround was more narrow than in AC, which could account for the larger-scale network dynamics in PPC. The more narrow central positive influence zone and wider suppressive surround in AC could serve to sharpen sensory representations.

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.

The cerebellum is critical for coordinating movements related to eating, drinking and swallowing, all of which require proper control of the tongue. Cerebellar Purkinje cells can encode tongue movements, but it is unclear how their simple spikes and complex spikes induce changes in the shape of the tongue that contribute to goal‐directed movements. To study these relations, we recorded and stimulated Purkinje cells in the vermis and hemispheres of mice during spontaneous licking from a stationary or moving water spout. We found that Purkinje cells can encode rhythmic licking with both their simple spikes and complex spikes. Increased simple spike firing during tongue protrusion induces ipsiversive bending of the tongue. Unexpected changes in the target location trigger complex spikes that alter simple spike firing during subsequent licks, adjusting the tongue trajectory. Furthermore, we observed increased complex spike firing during behavioural state changes at both the start and the end of licking bouts. Using machine learning, we confirmed that alterations in Purkinje cell activity accompany licking, with different Purkinje cells often exerting heterogeneous encoding schemes. Our data highlight that directional movement control is paramount in cerebellar function and that modulation of the complex spikes and that of the simple spikes are complementary during acquisition and execution of sensorimotor coordination. These results bring us closer to understanding the clinical implications of cerebellar disorders during eating, drinking and swallowing. image Key points When drinking, mice make rhythmic tongue movements directed towards the water source. Cerebellar Purkinje cells can fire rhythmically in tune with the tongue movements. Purkinje cells encode changes in the position of the water source with complex spikes. Purkinje cell simple spike firing affects the direction of tongue movements. Purkinje cells that report changes in the position of the target can also adjust movements in the right direction.

Implantable neural electrode arrays can be inserted in the brain to provide single‐cell electrophysiology recording for neuroscience research and brain–machine interface applications. However, maintaining signal quality over time is complicated by inflammatory tissue responses and degradation of electrode materials. Organic electrode coatings offer a solution by enhancing recording and stimulation capabilities, including reduced impedance, increased charge injection capacity, and the ability to incorporate and release anti‐inflammatory drugs. Herein, acid‐functionalized multiwalled carbon nanotubes (CNTs) loaded with dexamethasone (Dex) are incorporated into poly(3,4‐ethylendioxythiophene) (PEDOT) as electrode coatings. The electrochemical stability and recording performance of the PEDOT/CNT/Dex coating over an extended period of ≈18 months are investigated. Cyclic voltammetry (CV) stimulation is used to release Dex in half of the recording sites during the first 11 days of implantation to reduce the acute inflammation. The PEDOT/CNT/Dex‐coated floating microelectrode arrays demonstrate stable in vivo electrode impedance and successful detection of visually evoked neural activity from the rat visual cortex even at chronic time points. Additionally, the CV‐stimulated sites exhibit higher single‐unit (SU) recording yield, amplitudes, and signal‐to‐noise ratio compared to unstimulated sites. These results highlight the potential of anti‐inflammatory treatments to improve the quality and longevity of chronic neural recordings.

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.

We hypothesized that active outer hair cells drive cochlear fluid circulation. The hypothesis was tested by delivering the neurotoxin, kainic acid, to the intact round window of young gerbil cochleae while monitoring auditory responses in the cochlear nucleus. Sounds presented at a modest level significantly expedited kainic acid delivery. When outer-hair-cell motility was suppressed by salicylate, the facilitation effect was compromised. A low-frequency tone was more effective than broadband noise, especially for drug delivery to apical locations. Computational model simulations provided the physical basis for our observation, which incorporated solute diffusion, fluid advection, fluid–structure interaction, and outer-hair-cell motility. Active outer hair cells deformed the organ of Corti like a peristaltic tube to generate apically streaming flows along the tunnel of Corti and basally streaming flows along the scala tympani. Our measurements and simulations coherently suggest that active outer hair cells in the tail region of cochlear traveling waves drive cochlear fluid circulation.

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.

The temporal structure of sensory inputs contains essential information for their interpretation. Sensory cortex represents these temporal cues through two codes: the temporal sequences of neuronal activity and the spatial patterns of neuronal firing rate. However, it is unknown which of these coexisting codes causally drives sensory decisions. To separate their contributions, we generated in the mouse auditory cortex optogenetically driven activity patterns differing exclusively along their temporal or spatial dimensions. Mice could rapidly learn to behaviorally discriminate spatial but not temporal patterns. Moreover, large-scale neuronal recordings across the auditory system revealed that the auditory cortex is the first region in which spatial patterns efficiently represent temporal cues on the timescale of several hundred milliseconds. This feature is shared by the deep layers of neural networks categorizing time-varying sounds. Therefore, the emergence of a spatial code for temporal sensory cues is a necessary condition to efficiently associate temporally structured stimuli with decisions.

Hearing is an active process in which listeners must detect and identify sounds, segregate and discriminate stimulus features, and extract their behavioral relevance. Adaptive changes in sound detection can emerge rapidly, during sudden shifts in acoustic or environmental context, or more slowly as a result of practice. Although we know that context- and learning-dependent changes in the sensitivity of auditory cortical (ACX) neurons support many aspects of perceptual plasticity, the contribution of subcortical auditory regions to this process is less understood. Here, we recorded single- and multiunit activity from the central nucleus of the inferior colliculus (ICC) and the ventral subdivision of the medial geniculate nucleus (MGV) of male and female Mongolian gerbils under two different behavioral contexts: as animals performed an amplitude modulation (AM) detection task and as they were passively exposed to AM sounds. Using a signal detection framework to estimate neurometric sensitivity, we found that neural thresholds in both regions improve during task performance, and this improvement is largely driven by changes in the firing rate rather than phase locking. We also found that ICC and MGV neurometric thresholds improve as animals learn to detect small AM depths during a multiday perceptual training paradigm. Finally, we revealed that in the MGV, but not the ICC, context-dependent enhancements in AM sensitivity grow stronger during perceptual training, mirroring prior observations in the ACX. Together, our results suggest that the auditory midbrain and thalamus contribute to changes in sound processing and perception over rapid and slow timescales.

Background Fragile X syndrome (FXS) is a leading known genetic cause of intellectual disability and autism spectrum disorders (ASD)-associated behaviors. A consistent and debilitating phenotype of FXS is auditory hypersensitivity that may lead to delayed language and high anxiety. Consistent with findings in FXS human studies, the mouse model of FXS, the Fmr1 knock out (KO) mouse, shows auditory hypersensitivity and temporal processing deficits. In electroencephalograph (EEG) recordings from humans and mice, these deficits manifest as increased N1 amplitudes in event-related potentials (ERP), increased gamma band single trial power (STP) and reduced phase locking to rapid temporal modulations of sound. In our previous study, we found that administration of the selective serotonin-1 A (5-HT 1A )receptor biased agonist, NLX-101, protected Fmr1 KO mice from auditory hypersensitivity-associated seizures. Here we tested the hypothesis that NLX-101 will normalize EEG phenotypes in developing Fmr1 KO mice. Methods To test this hypothesis, we examined the effect of NLX-101 on EEG phenotypes in male and female wildtype (WT) and Fmr1 KO mice. Using epidural electrodes, we recorded auditory event related potentials (ERP) and auditory temporal processing with a gap-in-noise auditory steady state response (ASSR) paradigm at two ages, postnatal (P) 21 and 30 days, from both auditory and frontal cortices of awake, freely moving mice, following NLX-101 (at 1.8 mg/kg i.p.) or saline administration. Results Saline-injected Fmr1 KO mice showed increased N1 amplitudes, increased STP and reduced phase locking to auditory gap-in-noise stimuli versus wild-type mice, reproducing previously published EEG phenotypes. An acute injection of NLX-101 did not alter ERP amplitudes at either P21 or P30, but significantly reduces STP at P30. Inter-trial phase clustering was significantly increased in both age groups with NLX-101, indicating improved temporal processing. The differential effects of serotonin modulation on ERP, background power and temporal processing suggest different developmental mechanisms leading to these phenotypes. Conclusions These results suggest that NLX-101 could constitute a promising treatment option for targeting post-synaptic 5-HT 1A receptors to improve auditory temporal processing, which in turn may improve speech and language function in FXS.

Sniffing is a motivated behavior displayed by nearly all terrestrial vertebrates. While sniffing is associated with acquiring and processing odors, sniffing is also intertwined with affective and motivated states. The systems which influence the display of sniffing are unclear. Here, we report that dopamine release into the ventral striatum in mice is coupled with bouts of sniffing and that stimulation of dopaminergic terminals in these regions drives increases in respiratory rate to initiate sniffing whereas inhibition of these terminals reduces respiratory rate. Both the firing of individual neurons and the activity of post-synaptic D1 and D2 dopamine receptor-expressing neurons are coupled with sniffing and local antagonism of D1 and D2 receptors squelches sniffing. Together, these results support a model whereby sniffing can be initiated by dopamine's actions upon ventral striatum neurons. The nature of sniffing being integral to both olfaction and motivated behaviors implicates this circuit in a wide array of functions.

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.

The ability of the brain to process auditory information across multiple temporal scales is crucial for perception. This study introduces an innovative experimental approach using nonlinguistic structured stimuli composed of click trains that alternate at different rates to investigate auditory processing across 3 distinct temporal scales: individual clicks (tens of milliseconds), click trains forming auditory objects (hundreds of milliseconds), and higher-order click trains in neuronal novelty detection (seconds) in both rhesus monkeys and humans. Electrocorticography recordings in the auditory cortex of rhesus monkeys unveil the primate brain’s remarkable ability to process intricate auditory temporal patterns at timescales of tens and hundreds of milliseconds. Furthermore, extracellular recordings in monkeys demonstrate pronounced responsiveness to deviant click trains at longer temporal scales in the primary auditory cortex (A1), accompanied by synchronization with both individual clicks and click trains. By contrast, neurons in the auditory thalamus prefer individual clicks only. Notably, neurons in A1 exhibit the ability to synchronize with individual clicks while simultaneously integrating these clicks into cohesive train objects, a phenomenon we term “temporal integration during synchronization”. Additional human electroencephalography recordings complement and support these findings, highlighting the paradigm’s potential for clinical applications. Our research offers novel insights into the neural mechanisms underpinning auditory information processing across various temporal scales at the neuronal level.