The Journal of Neuroscience

Auditory learning enables sound-selective enhancements in auditory cortical (AC) processing. Background noise can also alter sound-selective auditory responsivity. Yet, how learning can enhance AC processing in noise is unknown. Pharmacological inhibition of histone deacetylase 3 (HDAC3) via RGFP966 enhances learning and related AC plasticity, but its potential to support signal detection under degraded acoustic conditions is unclear. To determine if task learning supports tone-signal detection in a later background noise challenge, adult rats (Sprague-Dawley males) were trained in ideal quiet conditions to learn a tone-reward association while treated with RGFP966 (TRAINED+RGFP966, n=6). RGFP966 accelerated sound-reward learning relative to untreated rats (TRAINED, n=5), though all animals reached equivalent high levels of performance before further testing. Successful performance produced sound-specific enhancements in AC responses evoked by the learned tone, and a sound-general effect that suppressed responses to noise, relative to untrained rats (NAIVE, n=7). Notably, frequency-selective response biases were latent under quiet conditions and became robustly expressed under background noise, particularly in RGFP966-treated learners who acquired the task more rapidly. Increasing background noise abolished frequency-selective enhancements in tone-evoked AC activity, yet the learning-induced suppressive effect to noise was maintained. Behavioral detection of the learned tone across noise conditions mirrored AC tone-evoked response patterns. The findings demonstrate that learning can engage coordinated cortical mechanisms regulated by HDAC3 that selectively modify representations of behaviorally relevant signals. Further, auditory memory is dynamically gated by sensory context, relying on the stability of cortical decoding mechanisms to support listening in real-world environments. SIGNIFICANCE STATEMENTDifficulty hearing in noise is a widespread challenge, yet the cortical mechanisms that preserve meaningful sounds under noisy listening conditions remain unclear. We show that HDAC3 inhibition via the pharmacological inhibitor, RGFP966, accelerates auditory learning and strengthens cortical encoding of a learned tone while suppressing background noise activity in ways that predict improved behavioral detection. These findings reveal an experience-driven cortical mechanism that supports improved hearing in challenging listening environments, which may inform strategies for enhancing auditory learning and rehabilitation using HDAC3 drug-targets.

Dopaminergic brain areas are crucial for cognition and their dysregulation is linked to neuropsychiatric disorders typically treated with pharmacological interventions. These treatments often have side effects and variable effectiveness, underscoring the need for alternatives. We introduce the first demonstration of neurofeedback using local field potentials (LFP) from the ventral tegmental area (VTA). This approach leverages the real-time temporal resolution of LFP and ability to target deep brain. In our study, non-human primates learned to regulate VTA beta power using a customized normalized metric to stably quantify VTA LFP signal modulation. The subjects demonstrated flexible and specific control with different strategies for specific frequency bands, revealing new insights into the plasticity of VTA neurons contributing to oscillatory activity that is functionally relevant to many aspects of cognition. Excitingly, the subjects showed transferable patterns, a key criterion for clinical applications beyond training settings. This work provides a foundation for neurofeedback-based treatments, which may be a promising alternative to conventional approaches and open new avenues for understanding and managing neuropsychiatric disorders. Significance statementThis study demonstrates, for the first time, that neurofeedback using local field potentials (LFP) from the ventral tegmental area (VTA) is feasible in non-human primates. By leveraging the temporal resolution and ability to target deep brain regions, this approach provides a novel way to modulate brain activity linked to dopamine-related functions. The findings reveal that subjects can flexibly control VTA LFP signals and transfer learned strategies to new settings, offering potential for developing neurofeedback-based treatments. This research opens new avenues for managing neuropsychiatric disorders, presenting an alternative to traditional pharmacological interventions that often have side effects and limited effectiveness. The study highlights the plasticity of VTA neurons and their relevance to cognition and mood regulation.

Foraging requires animals to integrate spatial, temporal, and reward-related costs to guide adaptive action selection, yet how neurodegenerative pathology alters this process remains poorly understood. We compared foraging behavior in control (C57BL/6J) and APPNL-G-F transgenic mice, a knock-in mouse model of Alzheimer disease. The foraging task was structured such that distance to home, the size of food-pellet rewards, and food texture jointly shaped choices. These task variables implicitly imposed time costs related to travel, handling, and inter trial intervals. While control mice adjusted foraging behavior in relation to task demands across conditions, APPNL-G-F mice showed systematic deviations from control patterns. Their choices were characterized by increased withdrawal and reduced flexibility as spatial and temporal costs increased. Using a normative rate-maximization framework grounded in classical foraging theory, we quantified optimality and found marked suboptimality in both groups: control mice achieved 53% of the optimal reward rate, whereas APPNL-G-F mice achieved 45%. This suboptimality indicates that naturalistic decision making operates under context-dependent constraints rather than adhering to strict theoretical optimality. Within this constrained landscape, APPNL-G-F mice deviated more strongly from optimality than control mice, particularly under conditions requiring fine-grained integration of time-based costs. Group differences were most pronounced when optimal policies were highly sensitive to small errors in the estimation of temporal and spatial trade-offs. These findings suggest that Alzheimer-related pathology selectively amplified normative decision deficits rather than producing qualitatively distinct foraging strategies.

Development is a time of great opportunity. A heightened period of neural plasticity contributes to dramatic improvements in perceptual, motor, and cognitive skills. However, developmental plasticity poses a risk: greater malleability of neural circuits exposes them to environmental factors that may impede behavioral maturation. While these risks are well-established prior to sexual maturity (i.e., critical periods), the degree of neural vulnerability during adolescence remains uncertain. To address this question, we induced a transient period of hearing loss (HL) spanning adolescence in the gerbil, confirmed by assessment of circulating sex hormones, and asked whether behavioral and neural deficits are diminished. Wireless recordings were obtained from auditory cortex neurons during perceptual task performance, and within-session behavioral and neural sensitivity were compared. We found that a transient period of adolescent HL caused a significant perceptual deficit (i.e., amplitude modulation detection thresholds) that could be attributed to degraded auditory cortex processing, as confirmed with both single neuron and population-level analyses. In contrast, perceptual deficits did not occur when HL of the same duration was induced in adulthood. To determine whether degraded auditory cortex encoding was attributable to an intrinsic change, we obtained auditory cortex brain slices from adolescent HL animals, and recorded synaptic and discharge properties from auditory cortex pyramidal neurons. There was a clear and novel phenotype, distinct from critical period HL: excitatory postsynaptic potential amplitudes were elevated in adolescent HL animals, whereas inhibitory postsynaptic potentials were unchanged. This is in contrast to critical period deprivation, where there are large changes to synaptic inhibition. Taken together, these results show that diminished adolescent sensory experience can cause long-lasting behavioral deficits that originate, in part, from a dysfunctional cortical circuit. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/439537v2_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@50b787org.highwire.dtl.DTLVardef@1410662org.highwire.dtl.DTLVardef@a0fa6org.highwire.dtl.DTLVardef@897b1c_HPS_FORMAT_FIGEXP M_FIG Summary of experimental design and main findings. C_FIG

Monocular deprivation (MD) causes an initial decrease in synaptic responses to the deprived eye in juvenile mouse primary visual cortex (V1) through Hebbian long-term depression (LTD). This is followed by a homeostatic increase, which has been attributed to synaptic scaling. However, homeostasis during other forms of visual deprivation is caused by sliding the threshold for Hebbian long-term potentiation (LTP) rather than scaling. We therefore asked whether the homeostatic increase during MD requires GluN2B-containing NMDA receptor activity, which is required to slide the plasticity threshold but not for synaptic scaling. Selective GluN2B blockade from 2-6d after monocular lid suture prevented the homeostatic increase in miniature excitatory postsynaptic current (mEPSC) amplitude in monocular V1 of acute slices and prevented the increase in visually evoked responses in binocular V1 in vivo. The decrease in mEPSC amplitude and visually evoked responses during the first 2d of MD also required GluN2B activity. Together, these results indicate that GluN2B-containing NMDA receptors first play a role in LTD immediately following eye closure, and then promote homeostasis during prolonged MD by sliding the plasticity threshold in favor of LTP.

When adult mice are repeatedly exposed to a particular visual stimulus for as little as one hour per day for several days while their visual cortex (V1) is in the high-gain state produced by locomotion, that specific stimulus elicits much stronger responses in V1 neurons for the following several weeks, even when measured in anesthetized animals. Such stimulus-specific enhancement (SSE) is not seen if locomotion is prevented. The effect of locomotion on cortical responses is mediated by vasoactive intestinal peptide (VIP) positive interneurons, which can release both the peptide and the inhibitory neurotransmitter GABA. Here we used genetic ablation to determine which of those molecules secreted by VIP-ergic neurons is responsible for SSE. SSE was not impaired by VIP deletion but was prevented by compromising release of GABA from VIP cells. This finding suggests that SSE may result from Hebbian mechanisms that remain present in adult V1. SIGNIFICANCEMany neurons package and release a peptide along with a conventional neurotransmitter. The conventional view is that such peptides exert late, slow effects on plasticity. We studied a form of cortical plasticity that depends on the activity of neurons that express both vasoactive intestinal peptide (VIP) and the inhibitory neurotransmitter GABA. GABA release accounted for their action on plasticity, with no effect of deleting the peptide on this phenomenon.

Auditory neurons, in the midbrain and beyond, detect changes in repeating acoustic patterns. Most studies focus on mechanisms underlying such sensitivity and adaptation to regularity. However, regular sound patterns are crucial in social communication, stream-segregation and grouping in different species including humans. Thus, we address cortical selectivity to periodic or aperiodic sound sequences with multiple stimulus attributes. With single unit electrophysiology and two-photon calcium imaging in anesthetized and awake mouse auditory cortex, we observe subpopulations of neurons selective to periodicity or aperiodicity that lack generalization across period-length, frequency-content or inter-token-interval durations. Comparing results with or without inter-token-interval spiking activity, shows its profound role underlying selectivity to periodic or aperiodic sequences. The whole population average rate for periodic and aperiodic stimuli is identical but not following each period and stimulus-off-period. Hence, inter-token-interval activity, post each period increases during the sequence providing information on selectivity and a prediction like signal. HighlightsO_LIContrary to common view, subpopulations of neurons in the auditory cortex are selective to repetitive sound patterns or periodic sound sequences and another to aperiodic ones. C_LIO_LINeither population of neurons above generalizes their selectivity across properties of tokens of the sequences. C_LIO_LINeural activity during the inter-token interval plays an important role in enhancing the observed selectivity. C_LIO_LIPost period or pre-subsequent period activity builds up during the stimulus providing a prediction like signal for periodic sequences with respect to aperiodic sequences. C_LI

Decision-making is influenced by both expected reward and social factors, such as who offered the outcomes. Thus, although a reward might originally be independent from social factors, the two elements are closely related. However, whether and how they are processed separately or conjointly remains unclear. Here, we show that neurons in distinct sub-nuclei of the amygdala encode expected reward and face animacy, which is a vital aspect of face perception. Although these encoding processes are distinct, they rely on partially shared neuronal circuits with characteristic temporal dynamics. Two male macaque monkeys made saccades under different social and reward contexts, created by presenting facial images with independent attributes: animacy (a monkey or cartoon face) and associated reward (large or small). The stimulus image was presented twice per trial: during the initial stimulus encoding (S1) and before saccades were made (S2). A longer gaze duration for eye region of the monkey versus cartoon images indicated more robust social engagement for realistic faces. During S1, a similar number of lateral nucleus neurons encoded either animacy only with a monkey-image preference, reward only with a large-reward preference, or both. Conversely, neurons in the basal and central nuclei primarily encoded reward, preferring large-versus small-reward associated face images. The reward-dependent modulation was continuous after S1, but was more conspicuous during S1 in the basal nucleus and during both S1 and S2 in the central nucleus. This anatomically- and temporally-specific encoding in the amygdala may underlie the computation and integration of face animacy and reward information. Significance StatementReward and social information are closely related but originally independent, as both influence our decision-making. The amygdala has been associated with both reward and social information coding. However, whether and how they are processed separately or conjointly by individual neurons in the amygdala remains unclear. We found that neurons in the lateral and basal nuclei encoded face animacy, which is an important aspect of social information, and reward, respectively, during sensory processing. Neurons in the central nucleus encoded reward information during the execution phase. This provides new clarity regarding the mechanisms of separate or integrated social and reward information processing within the amygdala.

For a long time, myelin was thought to be restricted to excitatory neurons, and studies on dysmyelination focused primarily on excitatory cells. Recent evidence showed that axons of inhibitory neurons in the neocortex are also myelinated, but the role of myelin on inhibitory circuits remains unknown. Here we studied the impact of mild hypomyelination on both excitatory and inhibitory connectivity in the primary auditory cortex (A1) with well-characterized mouse models of hypomyelination due to loss of oligodendrocyte ErbB receptor signaling. Using laser-scanning photostimulation, we found that mice with mild hypomyelination have reduced functional inhibitory connections to A1 L2/3 neurons without changes in excitatory connections, resulting in altered excitatory/inhibitory balance. These effects are not associated with altered expression of GABAergic and glutamatergic synaptic components, but with reduced density of parvalbumin-positive (PV+) neurons, which reflects reduced PV expression by interneurons rather than PV+ neuronal loss. While immunostaining shows that hypomyelination occurs in both PV+ and PV- axons, there is a strong correlation between MBP and PV expression suggesting that myelination influences PV expression. Together, the results demonstrate that mild hypomyelination impacts A1 neuronal networks, reducing inhibitory activity, and shifting networks towards excitation.

Sound perception is closely linked to the spatiotemporal patterning of neural activity in the auditory cortex (ACtx). Inhibitory interneurons sculpt the patterns of excitatory ACtx pyramidal neuron activity, and thus play a central role in sculpting the perception of sound. Reduced inhibition from parvalbumin-expressing (PV) inhibitory interneurons and the associated increased gain of sound-evoked pyramidal neuron spike rates are well-established consequences of aging and sensorineural hearing loss. Here, we reasoned that changes in PV-mediated inhibition would directly impact the perception of loudness. We hypothesized that ACtx PV activity could function as a perceptual volume knob, where reduced or elevated PV activity would increase or decrease the perceived loudness of sound, respectively. To test these hypotheses, we developed a two-alternative forced-choice loudness classification task for head-fixed mice and demonstrated that noise-induced sensorineural hearing loss directly caused a [~]10 dB loudness hyperacusis that begins hours after noise-induced sensorineural hearing loss and persists for at least several weeks. Conversely, sounds were perceived as [~]10 dB softer during optogenetic activation of ACtx PV neurons without having any effect on the overall detectability of sound. These data suggest that ACtx PV neurons can bi-directionally control the perceived loudness of sound, presumably via the strength of their inhibition onto local pyramidal neurons. Further, these data identify cortical PV neurons as a target for hyperacusis therapies and demonstrate a direct link between acquired sensorineural hearing loss and loudness hyperacusis.

The subthalamic nucleus (STN) plays critical roles in the motor and cognitive function of the basal ganglia (BG), but the exact nature of these roles is not fully understood, especially in the context of decision-making based on uncertain evidence. Guided by theoretical predictions of specific STN contributions, we used single-unit recording and electrical microstimulation in the STN of healthy monkeys to assess its causal, computational roles in visual-saccadic decisions based on noisy evidence. The recordings identified subpopulations of STN neurons with distinct task-related activity patterns that related to different theoretically predicted functions. Microstimulation caused changes in behavioral choices and response times that reflected multiple contributions to an "accumulate-to-bound"-like decision process, including modulation of decision bounds and evidence accumulation, and to non-perceptual processes. These results provide new insights into the multiple ways that the STN can support higher brain function.

In contrast to most transgenic mouse models of Alzheimer disease (AD), knock-in mice expressing familial AD-linked mutations of the amyloid precursor protein (App) gene exhibit stereotypical age-dependent amyloid beta (A{beta}) pathology and cognitive impairment without physiologically unrealistic App overexpression. This study investigated the effect of familial AD-linked App mutations on hippocampal CA1 neuronal activity and function. To enable calcium imaging of neuronal activity, AppNL-G-F/NL-G-F knock-in (APPki) mice were crossed with Thy1-GCaMP6s+/- (C-TG) mice to generate AppNL-G-F/NL-G-FxThy1-GCaMP6s+/- (A-TG) mice, which were characterized at 12 months of age. A-TG mice exhibited A{beta} pathology in the hippocampus. In several configurations of an air-induced running task, A-TG mice and C-TG mice were equally successful in learning to run or to stay immobile. In the Morris water place test, A-TG mice were impaired, but learned the task. Comparisons of hippocampal CA1 neuronal activity in the air-induced running task showed that A-TG mice displayed neuronal hypoactivity both during movement and immobility. A-TG mice and C-TG CA1 neuronal encoding of distance or time in the air induced running task were not different. These results suggest that knock-in of familial AD-linked mutations in A-TG mice results in A{beta} pathology, neuronal hypoactivity, and cognitive impairment without severely affecting CA1 neuronal encoding. In comparison to APPki mice, A-TG mice had less severe AD-like memory impairments at 12 months of age (Saito et al., 2014; Mehla et al., 2019), suggesting that the disease onset was delayed in A-TG mice. The effect of APP mutations may have been mitigated through genetic mechanisms when APPKi mice were crossed with C-TG mice.

Acetylcholine (ACh) and serotonin (5-hydroxytryptamine, or 5-HT) differentially regulate the excitability of pyramidal neurons in the mouse prelimbic (PL) cortex according to their long-distance projections. Here we tested for afferent- and/or target-specific modulation of glutamate release by ACh and 5-HT in two long-distance excitatory projections to the PL cortex: commissural (COM) afferents from the contralateral cortex and projections from the mediodorsal nucleus (MDN) of the thalamus. Using ex-vivo optogenetic approaches, we mapped the connectivity and neuromodulation of COM and MDN afferents in layer 5 intratelencephalic (IT) and extratelencephalic (ET) projection neurons. Dual whole-cell recordings in pairs of IT and ET neurons revealed that COM afferents target both neuron subtypes, but that MDN afferents selectively target IT neurons. Both afferents exhibited similar target-independent short-term synaptic plasticity (paired-pulse facilitation) across a range of frequencies, but were differentially modulated by ACh and 5-HT. In both control conditions and after isolating monosynaptic connections with tetrodotoxin and 4-aminopyridine, COM transmission was suppressed strongly by ACh and moderately by 5-HT, while MDN transmission was largely unaffected by either neuromodulator. Suppression o,f COM transmission by ACh or 5-HT was concentration dependent and mediated by M4 muscarinic or 5-HT1B receptors, respectively. Chemogenetic inhibition of hM4Di-expressing COM terminals mimicked the suppressive effects of ACh and 5-HT on synaptic transmission. Our results demonstrate that ACh and 5-HT preferentially regulate COM synaptic transmission, albeit to different degrees, and suggest that, through their combined pre- and postsynaptic neuromodulation, ACh and 5-HT may differentially regulate cortico-striatal-thalamic loops to influence cognition and behavior.

Animals, including humans, use prediction error to guide learning about danger in the environment. The basolateral amygdala (BLA) is obligatory for this learning and BLA excitatory projection neurons are instructed by aversive prediction error to form fear associations. Complex networks of inhibitory interneurons, dominated by parvalbumin (PV) expressing GABAergic neurons, form the intrinsic microcircuitry of the BLA to control projection neuron activity. Whether BLA PV interneurons are also sensitive to prediction error and how they use this error to control fear learning remains unknown. We used PV cell-type specific recording and manipulation approaches in male transgenic PV-Cre rats to address these issues. We show that BLA PV neurons control fear learning about aversive events but not learning about their omission. Furthermore, during fear learning BLA PV neurons express the activity signatures of aversive prediction error: greater activity to unexpected than expected aversive events and greater activity to better rather than poorer predictors of these events. Crucially, we show that BLA PV neurons act to limit fear learning across these variations in prediction error. Together, this demonstrates that prediction error instructs and regulates BLA fear association formation in a cell-type specific manner. Whereas BLA projection neurons use prediction error signals to form and store fear associations, BLA PV interneurons use prediction error signals to constrain fear association formation. Significance StatementThe capacity to predict sources of danger in the environment is essential for survival. This capacity is supported by associative learning mechanisms that are triggered when the danger experienced is greater than the danger expected. Here we show that the activity of parvalbumin positive GABAergic interneurons in the rat basolateral amygdala neurons report this difference between the danger expected and the danger experienced and that they use this difference to limit the amount of fear which is learned.

The medial habenula (MHb) is implicated in regulating emotional responses to aversive events. Studies in zebrafish have identified a remarkable morphological left-right asymmetry in the dorsal habenula (zebrafish equivalent of mammalian MHb)-interpeduncular nucleus (IPN) pathway and its left-sided-specific role in modulating fear responses. However, there is little evidence for structural or functional lateralization in the mammalian MHb-IPN pathway. Here, we investigated the synaptic properties of left- and right-MHb afferents to the IPN and their roles in the expression of conditioned fear in mice. We found that each IPN neuron receives inputs from both left and right MHb, but the left MHb-originating synapses exhibit lower release probability and higher {gamma}-aminobutyric acid type B receptor (GABABR)-mediated potentiation compared to the right MHb-originating synapses. Interestingly, these asymmetrical properties persist in the inversus visceral mutant mice with normal internal organ laterality (situs solitus), but nearly disappear in those with reversed internal organ laterality (situs inversus). Behaviorally, chemogenetic inhibition of cholinergic neurons and conditional deletion of GABABR in the left, but not the right, MHb significantly attenuated cue-dependent fear recall. Our results demonstrate functional asymmetry of the MHb under partial influence of the nodal flow in mice, revealing a predominant role of GABABR-mediated signaling in the left MHb-IPN pathway in modulating fear memories. These findings suggest that lateralized MHb pathways could represent a fundamental principle in the neural regulation of emotion across species, but that they develop differently in zebrafish and mice.

Early sensory experience can exert lasting perceptual consequences. For example, a brief period of auditory deprivation early in life can lead to persistent spatial hearing deficits. Some forms of hearing loss (i.e., conductive; CHL) can distort acoustical cues needed for spatial hearing, which depend on inputs from both ears. We hypothesize that asymmetric acoustic input during development disrupts auditory circuits that integrate binaural information. Here, we identify prolonged maturation of the binaural auditory brainstem in the guinea pig by tracking auditory evoked potentials across development. Using this age range, we induce a reversible unilateral CHL and ask whether behavioral and neural maturation are disrupted. We find that developmental CHL alters a brainstem readout of binaural function which is not observed when the CHL is induced in adulthood. Startle-based behavioral measures reveal poorer spatial resolution of sound sources, but only for high-frequency sound stimuli. Finally, single-unit recordings of auditory midbrain neurons reveal significantly poorer neural acuity to a sound location cue that largely depends on high-frequency sounds. Thus, these findings show that unilateral deprivation can disrupt developing auditory circuits that integrate binaural information and may give rise to lingering spatial hearing deficits.

Mutations in FGF14, which encodes intracellular fibroblast growth factor 14 (iFGF14), have been linked to spinocerebellar ataxia type 27 (SCA27), a multisystem disorder associated with progressive deficits in motor coordination and cognitive function. Mice (Fgf14-/-) lacking iFGF14 display similar phenotypes, and we have previously shown that the deficits in motor coordination reflect reduced excitability of cerebellar Purkinje neurons, owing to the loss of iFGF14-mediated regulation of the voltage-dependence of inactivation of the fast transient component of the voltage-gated Na+ (Nav) current, INaT. Here, we present the results of experiments designed to test the hypothesis that loss of iFGF14 also attenuates the intrinsic excitability of mature hippocampal and cortical pyramidal neurons. Current-clamp recordings from adult mouse hippocampal CA1 pyramidal neurons in acute in vitro slices, however, revealed that repetitive firing rates were higher in Fgf14-/-, than in wild type (WT), cells. In addition, the waveforms of individual action potentials were altered in Fgf14-/- hippocampal CA1 pyramidal neurons, and the loss of iFGF14 reduced the time delay between the initiation of axonal and somal action potentials. Voltage-clamp recordings revealed that the loss of iFGF14 altered the voltage-dependence of activation, but not inactivation, of INaT in CA1 pyramidal neurons. Similar effects of the loss of iFGF14 on firing properties were evident in current-clamp recordings from layer 5 visual cortical pyramidal neurons. Additional experiments demonstrated that the loss of iFGF14 does not alter the distribution of anti-Nav1.6 or anti-ankyrin G immunofluorescence labeling intensity along the axon initial segments (AIS) of mature hippocampal CA1 or layer 5 visual cortical pyramidal neurons in situ. Taken together, the results demonstrate that, in contrast with results reported for neonatal (rat) hippocampal pyramidal neurons in dissociated cell culture, the loss of iFGF14 does not disrupt AIS architecture or Nav1.6 localization/distribution along the AIS of mature hippocampal (or cortical) pyramidal neurons in situ.

Adaptive behavior under threat requires deciding when to act and when to withhold action to avoid harm, often under conditions where movement, arousal, and task demand covary. Medial prefrontal cortex (mPFC) activity is widely associated with such control, yet it remains unclear whether this activity reflects causal action generation or broader evaluative processes shaped by behavioral state. Here, we combined fiber photometry, single-cell calcium imaging, mixed-effects modeling, and optogenetic inhibition to examine how GABAergic neurons in mouse mPFC represent cues, actions, and outcomes during a series of learned avoidance tasks of increasing complexity that promote cautious responding. By explicitly controlling for baseline activity and movement, we show that much apparent task-related activity in mPFC reflects movement and cue-evoked signals that are also present in a control cortical region, the visual cortex. mPFC GABAergic neurons showed little encoding of simple avoidance contingencies but broadly encoded punished outcomes. A small subset of neurons with strong movement sensitivity encoded more demanding avoidance contingencies requiring selection between action generation and deferment. For equivalent avoidance actions, distinct neuronal populations preferentially encoded either cue onset or the action. Despite this encoding, optogenetic inhibition of mPFC had minimal effects on the learning or performance of the different contingencies. These findings reveal a dissociation between neural encoding and causal necessity, indicating that mPFC GABAergic activity primarily reflects evaluative and contextual aspects of cautious avoidance behavior rather than direct control of action execution. Significance statementAvoiding danger often requires deciding when to act and when to hold back. The dorsomedial prefrontal cortex (mPFC) is widely assumed to support this control, yet the contributions of its neurons have remained unclear. Using neural population and single-neuron recordings together with targeted inhibition in mice performing learned threat-guided tasks, we show that GABAergic mPFC neurons are activated by cues, actions, and outcomes, but are not required for executing the behavior itself. These findings suggest that the mPFC primarily evaluates and contextualizes threat-motivated actions rather than generating them, highlighting a common mismatch between neural encoding and causal necessity. Synopsis for ReviewersNote the following organizational features: O_LIGiven the hierarchical structure of the experiments, all analyses use linear mixed-effects models, with sessions nested within mice as random effects. Models include relevant covariates, such as movement and baseline activity, to disentangle their contributions from task contingency-related effects. C_LIO_LITo facilitate reading flow, statistical details supporting the Results are reported in the figure legends. Additional statistical values can be provided or relocated to the main text if preferred. C_LIO_LIFigures and their legends are placed adjacent to the corresponding results to improve readability, but high-resolution versions are also at the end. In all population plots, the symbols, and traces are Mean{+/-}SEM. If error bars are not visible, they are smaller than the symbol and trace. We can adjust this as requested. C_LIO_LISeveral analyses are presented as supplemental figures to streamline the main narrative; figure order and presentation can be adjusted as requested. C_LI The Results are organized into six segments: O_LImPFC and visual cortex GABAergic neurons are sensitive to movement. Using fiber photometry, we show that GABAergic neurons in both mPFC and a control cortical region, visual cortex (VI), exhibit strong sensitivity to movement (Fig. 1; Fig. 1-S1). These findings motivated the inclusion of movement and baseline activity as covariates in neural analyses to control their effects. C_LIO_LIBehavioral performance across a series of avoidance tasks. Mice were trained in tasks of increasing difficulty (outlined in Fig. 2A). Animals were first exposed to three neutral cues (noUS), followed by cues predicting different contingencies. In AA19, CS1 signals active avoidance, and then in AA39, CS2 signals passive avoidance. Behavioral performance is shown in Fig. 2, associated movement traces in Fig. 2-S1, and mixed-effects models of movement dynamics in Fig. 2-S2. C_LIO_LIFiber photometry reveals limited encoding of simple avoidance but encoding of aversive outcomes. Fiber photometry recordings from mPFC and VI during the tasks show that mPFC GABAergic neurons do not robustly encode simple avoidance contingencies but exhibit sensitivity to more complex task demands and punished errors. Analyses also tested neural responses to unsignaled aversive stimulation. Results are shown in Fig. 3, with photometry traces in Fig. 3-S1 and a full model spanning all task phases in Fig. 3-S2. C_LIO_LISingle-cell recordings reveal movement-sensitive classes with distinct contingency encoding. Miniscope imaging was performed in mPFC during AA19 and AA39. Neurons were classified based on their correlation with movement and then tested for contingency encoding. This revealed class-specific differences, including a subset of neurons that encode avoidance-related variables. Results for AA19 are shown in Fig. 4, and for AA39 in Fig. 4-S1. C_LIO_LIAvoidance actions segregate into distinct movement modes with dissociable neural encoding. Avoidance actions were classified based on their movement profiles, revealing three response modes that differ in response latency and vigor, reflecting varying degrees of behavioral caution. Clustering neural activity within each mode identified neurons that selectively encode cue onset versus action execution (Fig. 5 and Fig. 5-S1). C_LIO_LIOptogenetic inhibition of mPFC has minimal effects on avoidance behavior. Using two complementary optogenetic approaches (eArch3.0 and Vgat-ChR2), we tested the causal contribution of mPFC neurons to avoidance behavior. Inhibition produced minimal effects on learning or performance across tasks. Behavioral effects and optogenetic validation are shown in Fig. 6. C_LI

Information in sound stimuli is conveyed from sensory hair cells to the cochlear nuclei by the firing of auditory nerve fibers (ANFs). For obvious ethical reasons, single unit recordings from the cochlear nerve have never been performed in human, thus functional hallmarks of ANFs are unknown. By filtering and rectifying the electrical signal recorded at the round window of gerbil cochleae, we reconstructed a peri-stimulus time response (PSTR), with a waveform similar to the peri-stimulus time histograms (PSTHs) recorded from single ANFs. Pair-by-pair analysis of simultaneous PSTR and PSTH recordings in gerbil provided a model to predict the rapid adaptation and spontaneous discharge rates (SR) in a population of ANFs according to their location in the cochlea. We then probed the model in the mouse, in which the SR-based distribution of ANFs differs from the gerbil. We show that the PSTR-based predictions of the rapid adaptation time constant and mean SR across frequency again matched those obtained by recordings from single ANFs. Using PSTR recorded from the human cochlear nerve in 8 normal-hearing patients who underwent cerebellopontine angle surgeries for a functional cranial-nerve disorders (trigeminal neuralgia or hemifacial spasm), we predicted a rapid adaptation of about 3 milliseconds and a mean SR of 23 spikes/s in the 4 kHz frequency range in human ANFs. Together, our results support the use of PSTR as a promising diagnostic tool to map the auditory nerve in humans, thus opening new avenues to better understanding neuropathies, tinnitus, and hyperacusis.

Perception of motion critically depends on detecting the speed and direction of moving stimuli. The primary visual cortex (V1) of some mammals, including primates and carnivores, exhibits functional organization for key receptive field properties such as orientation, direction, and spatial frequency; however, less is known about the organization of speed-tuned cells. While individual V1 neurons have been shown to exhibit speed selectivity, functional architecture for speed preference has been primarily reported in higher cortical areas such as primate area MT. Using multi-channel electrophysiology in anesthetized female ferrets, we investigated the joint tuning of V1 neurons for spatial frequency, temporal frequency, orientation/direction, and speed. We found significant clustering of cells tuned for speed and for speed preference within single electrode penetrations. We found that both simple and complex cells can exhibit speed tuning, and no strong variation across cortical layers. In reanalysis of intrinsic signal imaging data from cat V1, we observed repeating "hot spots" of high speed selectivity separated by "cold spots" with low tuning for speed. These findings indicate that a functional architecture for speed tuning is present within V1 itself and transmitted to downstream cortical regions. Significance StatementTo perceive moving objects, the visual system must detect both their direction and speed. The primary visual cortex, the first cerebral visual area to receive visual information from the retina via the lateral geniculate nucleus, plays a key role in this process. Here, we demonstrate that the primary visual cortex in carnivores contains speed-tuned neurons. Moreover, these neurons are organized into clustered "hot spots" that repeat across the cortical surface, suggesting a functional architecture for speed. While speed-tuned functional maps were previously thought to exist only in higher visual areas, such as area MT in primates, our findings reveal their presence at the level of primary visual cortex.