The Journal of Neuroscience

The lateral habenula (LHb) shapes reward and aversion learning via projections to midbrain monoaminergic centers. Recent studies have demonstrated significant genetic, anatomical, and electrophysiological diversity within the LHb. However, it remains unclear how genetic or intrinsic electrophysiological characteristics relate to in vivo neuronal activity patterns. Additionally, there are few descriptions of transgenic mouse lines labeling specific LHb neuronal subtypes. Here we describe spatial gene expression patterns, electrophysiological characteristics, and projection targets for specific subpopulations of neurons in the LHb targeted via existing transgenic mouse lines. Furthermore, we demonstrate that two genetically defined subpopulations differentially respond to value, prediction errors, and directional movement during flexible, reward-guided behavior. These findings indicate that specific, genetically targetable, neuronal subpopulations in LHb may control discrete aspects of motivated behavior through parallel circuits targeting serotonergic and dopaminergic midbrain centers.

ObjectiveNeural-only decoding performance does not identify how much prediction neural history adds beyond task structure or recent output. We tested how this increment changes when context and temporal information boundaries are made explicit. ApproachWe defined context-conditional neural gain as held-out error reduction from adding context-residualized neural history to a context model. Fully nested, whole-trial cross-fitting excluded predicted trials from nuisance preprocessing, fitting, and selection. Trial replacement tested reliance on correct neural-behavioral pairing. Matched-seed calibration and linear and nonlinear sensitivities accompanied two Neural Latents Benchmark datasets, nine paired LINK dates (18 development sessions), and 20 prespecified untouched LINK sessions from the same macaque. Main resultsIn LINK, fixed neural-only R2 near 0.31 coexisted with gains of 0.3012/0.3125 beyond phase, 0.0193/0.0209 beyond geometry by phase, and 0.0077/0.0098 beyond that context plus measured-output history for center-out/random-target tasks. Fully nested analysis retained positive means for two neural feature definitions; replacement made all four negative. Geometry-conditional spiking-band-power gain reduced context-model mean squared error by 4.92%. In the untouched sample, geometry-conditional gain was positive in 20/20 sessions (mean 0.02158), contracted to 0.00755 with measured-output history, and exceeded replacement in 20/20. MC_Maze showed gain 0.00051 beyond a strong template, whereas MC_RTT retained 0.06846 beyond lag-matched cursor history. Three prespecified nonlinear-neural random-feature maps preserved this contrast while changing magnitudes. SignificanceUnder the tested specifications, neural gain depended on context, information availability, and model family, and the residual correction depended on correct trial pairing. Neural-decoding reports should therefore state the outcome, context, temporal boundary, model class, grouped validation, and pairing control. The audit is predictive and model-relative, not causal.

Behavioral flexibility is crucial to animal survival in dynamic environments, and a failure to update actions in response to recent outcomes is a hallmark of many neuropsychiatric disorders. However, the cellular and circuit mechanisms in the brain that support behavioral flexibility remain poorly understood. Forms of short-term plasticity such as synaptic facilitation have been theorized to transiently maintain information in neural circuits, and flexibly modulate how circuits process information depending on recent activity. Despite theoretical support, there is no direct experimental evidence linking synaptic facilitation to flexible decision-making. Recently, the presynaptic calcium sensor Synaptotagmin-7 (Syt7) has been shown to be required for synaptic facilitation at many synapses in the mammalian brain. Here, we assess operant learning in male and female Syt7 KO mice to determine how facilitation contributes to learning both stable and dynamic reward contingencies. We find that Syt7 KO mice acquired stable contingencies similarly to wild-type controls. However, KO mice were impaired in learning dynamic contingencies, showed more perseverative responding, and were delayed in applying a new task rule to all trial types following reversal. Behavioral modeling revealed a reduced influence of recent trial history on decisions in KO mice compared to wild-type controls. The behavioral deficits could not be explained by differences in motivation or memory. These results suggest that synaptic facilitation supports adaptive decision-making and that disruptions of short-term plasticity impair animals ability to use recent outcomes to update behavior.

Encoding-related pupil responses predict later memory performance, but the neural mechanisms linking these autonomic dynamics to memory formation remain unclear. This study examined whether pupil responses during encoding track activity in the brains memory network and whether they reflect functional interactions between memory-related regions and neural systems involved in pupil control. Participants performed an incidental encoding task involving object stimuli while undergoing simultaneous fMRI and pupillometry; recognition memory was subsequently assessed outside the scanner. Greater pupil constriction during encoding predicted both the strength and quality of later memory. These pupil dynamics correlated with activity in memory-related brain regions, notably the hippocampus and the parahippocampal cortex. Connectivity analyses indicated that encoding-related pupil responses were supported by functional interactions between the hippocampus and the midbrain Edinger-Westphal nucleus, the striatum, and the orbitofrontal cortex. The findings suggest that interactions between memory-related regions and parasympathetic pupil-control systems may modulate encoding efficiency. Together, the results identify encoding-related pupil constriction as a non-invasive marker of memory-network engagement and suggest a hippocampal-midbrain pathway through which autonomic pupil dynamics are coupled with successful memory formation.

Congenital sensory loss reveals how experience shapes the brain organization, yet most accounts of such plasticity have focused on cortex rather than the thalamic systems that link sensory input, cortical development, and distributed networks. Here, we tested whether primary and higher-order thalamic nuclei show distinct relationships with thalamocortical organization after early sensory loss. In congenital blindness, structural differences were focal to the lateral geniculate nucleus (LGN), the primary thalamic nucleus of the visual system, with individual differences in LGN volume associated with areal features of primary visual cortex morphology. Functional differences, by contrast, involved altered relationships between visual cortex and higher-order cortical and thalamic systems, including stronger functional similarity between visual cortex and control-related networks at rest and during active nonvisual cognition. A parallel analysis of congenital deafness showed no detectable volumetric difference in the medial geniculate nucleus, the primary thalamic nucleus of the auditory system, but revealed altered functional relationships between auditory cortex and higher-order cortical and thalamic systems. These findings suggest that primary thalamic pathways are associated with modality-specific structural consequences of early sensory loss, whereas higher-order thalamocortical systems contribute to convergent functional reorganization of affected sensory cortices across sensory modalities.

Symmetry is a fundamental organizing principle of mid-level vision, yet which aspects of human symmetry processing are shared across primates remains unclear. Using steady-state visual evoked potentials during passive viewing, we compared responses to two well-matched wallpaper groups, double reflection (PMM) and four-fold rotation (P4), in common marmosets and humans, using identical stimuli. Marmosets showed robust reflection-symmetry responses comparable in relative magnitude, temporal dynamics and scalp distribution to those of humans. Rotation responses were also reliable but transient, lacking the sustained late component prominent in humans. This dissociation suggests that feedforward computations underlying symmetry detection are conserved across primates, whereas sustained processing that elaborates symmetry representations (likely recurrent or feedback in origin) is reduced in marmosets, particularly for rotation. These findings establish marmosets as a tractable model for symmetry processing and open a path to intracortical recording in accessible extrastriate cortex.

Theories of predictive coding propose that perception is the process of inferring the causes of our sensory input by comparing that input with predictions derived from our internal models of the world. Such predictive processes are thought to play a central role in language comprehension, however, robust neurophysiological evidence for such processes, particularly during natural speech perception, remains limited. Previous work has suggested that the early auditory encoding of words in natural speech is influenced by their preceding linguistic context. However, it remains unclear whether this effect is driven by prediction per se or dynamic modulations of attention based on contextual uncertainty. To distinguish between these alternatives, we recorded electroencephalography from 17 healthy adults while they listened to slightly changed audiobook. Specifically, we identified and replaced several unsurprising content words with more surprising words. We quantified the early auditory encoding of words using speech-envelope reconstruction accuracy within 100-ms time window after word onset and examined its relationship to word surprisal and contextual uncertainty. We found that more surprising words showed enhanced early auditory encoding despite matched contextual constraint. Moreover, the temporal profile of this enhancement depended on when the incoming speech signal diverged from the predicted phonological sequence, consistent with the emergence of prediction-error responses. Linear mixed-effects modeling further revealed that word surprisal had a substantially stronger influence on early auditory encoding than contextual uncertainty. Together, these findings indicate that the early auditory encoding of words during naturalistic speech perception is more strongly associated with predictive computations than with uncertainty-driven attentional gain. Significance StatementDuring natural speech comprehension, contextual information influences how the brain processes incoming sensory input. However, whether this context-dependent modulation of the early auditory encoding of words reflects predictive computations or dynamic changes in attentional gain has remained unresolved. By combining a naturalistic speech paradigm with a stimulus manipulation that varies word surprisal while controlling contextual uncertainty, we show that the early auditory encoding of words is driven by word surprisal under matched contextual constraint. Moreover, the temporal dynamics of this modulation closely follow the point at which the incoming speech signal departs from the predicted phonological sequence. These findings provide neurophysiological evidence that predictive computations contribute to the context- dependent modulation of early auditory processing during natural speech comprehension.

Excitatory synaptic plasticity within the nucleus accumbens (NAc) drives motivated behaviors, and dysregulation is implicated in several psychiatric disorders marked by impaired reward processing. The NAc integrates glutamatergic input, which conveys information about reward, context, and behavioral goals, with local GABAergic signaling that regulates excitatory transmission and medium spiny neuron (MSNs) output. However, little is known regarding GABA-dependent modulation of activity-dependent excitatory synaptic plasticity. Here, we investigated GABAB receptor (GABABR) regulation of plasticity at hippocampus (Hipp)-NAc synapses, at which plasticity is a key mediator of reward-related behaviors. Using whole-cell electrophysiological recordings in mouse brain slices, we found that pharmacological inhibition of GABABRs converts long-term potentiation (LTP) into long-term depression (LTD) selectively in females, identifying a sex-specific role for GABABRs in modulating long-term plasticity of Hipp-MSN synapses. This LTD required mGluR5 activation and estrogen receptor alpha (ER) in both D1- and D2-expressing MSN subtypes, while only D1-MSNs suggested that LTD was expressed presynaptically through a CB1 receptor-dependent mechanism. Notably, GABABR inhibition did not alter basal synaptic transmission, indicating a specific role for these receptors in gating plasticity beyond regulation of basal excitatory drive. Together, these findings identify a novel, sex-specific mechanism by which GABABRs control the direction of synaptic plasticity.

Reward is traditionally thought to drive value-dependent reinforcement processing, whereas recent work suggests reward may instead raise arousal that mimics reinforcement. Because reinforcement and arousal depend on partly distinct neuromodulatory systems yet are co-triggered by reward, they have been widely treated as closely linked, though rarely tested directly, leaving reward's physiological consequences difficult to interpret. We manipulated the value of a primary reward by varying thirst while independently inducing arousal with sound, and measured pupil diameter and electroencephalographic activity. High- and low-value rewards produced comparable pupil dilation, indicating value-independent arousal. In contrast, only high-value reward increased alpha-band power, progressing from anterior to posterior regions, whereas low-value reward and sound produced similar alpha suppression without regional progression. Thus, reward evokes two dissociable consequences: value-independent arousal and value-dependent reinforcement. Rather than a single coupled process, these arise through separable mechanisms, providing a physiological framework for distinguishing each mechanism's contribution to reward processing.

Reinforced conditioning allows individuals predicting future events with high confidence. However, many daily behaviours rely on unreinforced connections of neutral stimuli, called Incidental Associations (IAs), which enhance predictive capacity in unstable environments and are observed across species. IAs can be studied through sensory preconditioning paradigms, where two neutral stimuli (S1/S2) are presented together in a preconditioning phase, followed by classical conditioning of S1 with a potent reinforcer. As a result, subjects present a direct response to the S1 stimulus, but also display mediated responses to the S2 stimulus never explicitly reinforced, indicating IA formation during preconditioning. Our previous work demonstrated that type-1 cannabinoid receptors (CB1 receptors) in the hippocampus are essential for this IA formation. As dopamine signaling is also important for this process, we investigate the role of interactions between these dopamine-cannabinoid systems in IA memory formation in the hippocampus. Extending our previous work on odor-taste association, using light-sound association we showed that global CB1 receptor knock-out or specific hippocampal CB1 receptor deletion also blocked mediated responses to sound (S2) while direct response to light (S1) was unaltered. Focusing on dopamine, we then found hippocampal dopaminergic activity is enhanced during paired presentations of S1 and S2 and that blockade of dopamine D1 receptor during preconditioning S1-S2 associations abolished mediated response to S2. Interestingly, mice lacking CB1 receptors specifically in D1-receptor-expressing cells (D1-CB1-KO) failed to show mediated responses for either light-sound or odor-taste associations, identifying this CB1 receptor population as critical for IA formation. Enhanced activation of CB1 receptors, through either increase of endocannabinoids (using degradation enzyme inhibition) or exogenous stimulation by cannabis-derived Delta-9-tetrahydrocannabinol (THC), was able to promote the formation of IAs under insufficient conditions. The effect of endogenous CB1 activation, but not THC, was blocked in D1-CB1-KO mice indicating that IA-facilitation by endogenous and exogenous receptor activation rely on different mechanisms. Overall, these data uncover new mechanisms underlying unreinforced associative learning.

Human hand coordination exceeds that of other species, including great apes, and is marked by pronounced right-hand dominance. This specialization parallels an expansion of its cortical representation, forming the hand-knob in the motor cortex. In humans, this region shows high myelination on quantitative MRI (qMRI), but whether this feature is shared with great apes remains unclear. It is also unknown whether increased right-hand dominance in humans is mirrored by greater hemispheric asymmetry in cortical microstructure. Using high-resolution qMRI, we compared motor cortex subdivisions controlling the leg, hand, and face in humans and chimpanzees. We found consistently higher myelin and iron content in the hand-knob in both species, suggesting an evolutionarily conserved role. However, only humans showed enhanced rightward lateralization. These results highlight both conserved and species-specific features of the motor cortex, offering insights into the evolution of manual dexterity and handedness.

Unipolar brush cells (UBCs) are excitatory interneurons that have a characteristic dendritic brush that amplifies and extends incoming signals in the cerebellum. UBCs transform synaptic input through their ionotropic and metabotropic glutamate receptors. Differential regulation of receptor subunits is a critical developmental process, but how the expression of glutamatergic receptors changes in UBCs as they develop is unclear. NMDA-type glutamate receptors (NMDARs) are particularly important for development and plasticity. We examined the expression of NMDAR subunits during development and tested whether signaling through these receptors is necessary for the development of the elaborate dendritic structure and unusual synaptic function of UBCs. Whole-cell patch clamp recordings from UBCs in acute brain slices revealed tonic and synaptic NMDAR-mediated currents in early postnatal UBCs that decrease during development. RNAscope in situ hybridization revealed differential developmental regulation of GluN2C/D subunits. Cell-type specific constitutive NMDAR knockout had no apparent effect on dendritic brush development, but increased UBC number in adulthood, suggesting a role in programmed cell death. Both pharmacological blockade or genetic deletion of NMDARs produced a paradoxical increase in excitability, which was calcium dependent and was occluded by inhibition of calcium activated potassium channels. Thus, NMDA receptors are dispensable for migration and dendritic development but may be involved in cell death pathways. Their functional roles include synaptic signaling as well as providing a tonic calcium flux that dampens excitability in developing UBCs and may influence transformations of vestibular signals essential for smooth movements and balance.

PurposeThe neural representation of pitch and timbre in complex sounds has previously been studied using synthetic, controlled stimuli to investigate underlying encoding mechanisms. These studies provide information about how single attributes of sound are represented in the inferior colliculus (IC), a critical hub of the auditory pathway where neurons are sensitive to stimulus periodicity and spectral shape, giving rise to representations of pitch and timbre, respectively. However, there is a gap in understanding how natural sounds with both pitch and timbre attributes, such as instrument sounds, are represented in the IC. MethodsIn this study, extracellular recordings were made in the IC of awake rabbits in response to natural instrument stimuli varying in fundamental frequency (F0) to determine how instrument identity (timbre) and F0 (pitch) are represented in IC neurons. ResultsUsing decoding models for instrument identification, we found that instrument identity was redundantly encoded in a population of neurons with diverse rate and timing characteristics. F0 identification using decoding models trained on single-neuron rate responses was poor, but the population of rate responses contained enough information to identify F0 reliably. F0 information was also encoded in single-neuron temporal responses up to 196 Hz. F0 identification from a population of temporal responses was accurate up to approximately 900 Hz, but accuracy decreased at high F0s. For the task in which F0 was identified based on responses to both oboe and bassoon stimuli that had overlapping F0s, performance decreased compared to F0 identification based on responses to a single instrument. ConclusionThis result supports the hypothesis that pitch and timbre information are encoded jointly in the IC.

Lateral hypothalamic GABAergic (LHAGABA) neurons regulate arousal, feeding, and reward-related behaviors, but how their downstream projections coordinate motivated behaviors across domains remains incompletely defined. Our histological analyses revealed that LHAGABA fibers were distributed across the dorsal pons (DP) subregions, including the peri-locus coeruleus, laterodorsal tegmentum, and Barringtons nucleus, and extend throughout the lateral preoptic area (LPO), thereby refining existing anatomical descriptions. We then used optogenetics to systematically compare the effects of activating LHAGABA somata and their projections to the DP and LPO across assays of feeding, non-food-directed gnawing, predatory behavior, real-time place preference, and operant self-stimulation. In sated mice, optogenetic activation of LHAGABA somata or their terminals in the DP or LPO increased caloric food intake, whereas non-caloric cellulose intake was minimally affected during terminal stimulation. Across conditions, activation increased gnawing and shredding of non-food objects while reducing inactivity. In cricket hunting, stimulation increased cricket killing and consumption relative to controls. Similarly, all stimulation conditions supported positive-valence and reinforcement-related responding, as indicated by real-time place preference and operant self-stimulation. Together, these results provide new functional evidence that activation of LHAGABA somata and projections to both the DP and LPO recruit largely overlapping behavioral responses across feeding, non-food behavior, predatory hunting, and reinforcement-related assays. These findings support a distributed hypothalamic output architecture in which major ascending and descending LHAGABA pathways contribute to a shared motivational repertoire rather than wholly discrete behavioral functions.

Difficult decisions require gathering evidence over extended periods, placing demands on working memory. Yet, how working memory limitations affect decision-making remains largely unknown. We trained two macaque monkeys to perform a probabilistic reasoning task that involved extended sequential evidence sampling, requiring reliance on working memory. Monkeys made choices informed by a stream of briefly presented cues, each providing probabilistic evidence about which choice would be rewarded. In both animals, choices were significantly affected by working memory decay, primacy, recency, and priming. Despite individual differences in working memory limitations, both monkeys adopted sampling strategies that made their behavior nearly optimal. To test how dopamine affects working memory constraints on evidence accumulation, we systemically applied dopamine D1 receptor agonist and antagonist drugs midway during selected sessions. Activation of D1 receptors reduced priming. Blockade of D1 receptors reduced working memory decay and the subjective evidence weights assigned to individual cues. Our results reveal that complex decisions are constrained by working memory limitations and identify dopamine as a key modulator of this process, with potential implications for cognitive disorders and their treatment.

The coordination of sensory processing and working memory (WM) is fundamental to cognition. Spatial organization of sensory processing and WM is known to be broadly distributed across the cortex, but finer-scale organization at the interfaces between these functions remains understudied. Although the notion of sharp parcellations of cortex into distinct functional modules dominates the field, a growing body of works support graded changes in function and anatomy in some cortical zones. Based on this and potential advantages of gradient organizational structure in frontal cortex, we hypothesized that sensory-WM interfaces in the frontal cortex are gradient-like, not boundary-like. We examined twenty bilateral cortical regions that participate in visual/auditory WM tasks. In five frontal cortical regions, group-level WM activation overlapped with sensory drive, but was spatially shifted. We compared subject-level (N=20) boundary and gradient models of change in function. Strong individual-level evidence for sensory-WM gradients was observed in pre-supplementary motor area, ventral premotor cortex, and anterior insula in both modalities and in dorsal premotor cortex for visual WM. Conversely, dorsolateral pre-frontal cortex yielded mixed results, favored distinct WM and sensory regions in the left hemisphere, and gave some evidence for gradients in the right hemisphere. These results provide evidence that sensory and WM regions in frontal cortex are largely not distinct with sharp boundaries at their interfaces but instead bleed into each other to form local rostral-caudal sensory-WM gradients. We speculate these gradients may allow efficient interfacing between sensory and WM representations, and/or fine-grained, task-dependent shifting between bottom-up sensory and top-down influences.

Recent work has revealed two food-selective areas in the lateral and ventromedial occipitotemporal cortex (OTC). These studies have shown that food selectivity in these regions cannot be explained by mid-level features like shape, texture, or colour but differences in their representational content remain unclear. Across two fMRI experiments conducted in the same group of participants, we characterized the dimensions underlying food representations in lateral and ventral OTC by examining the contribution of action-related object properties, such as manipulability, relevant to object interaction, and visual features, such as colour and ensemble statistics, relevant to object recognition. Our results reveal a clear dissociation between lateral and ventral OTC, indicating that food representations in these regions reflect distinct computational constraints. In lateral OTC, food representations were primarily associated with action-related properties shared between food and other graspable objects, whereas in ventral OTC, food representations were sensitive to surface object properties, such as colour and ensemble configuration. Consistent with this distinction, lateral OTC showed greater sensitivity to individual objects against distinctive background and responded equally to colour and greyscale stimuli, while ventral OTC exhibited greater sensitivity to coloured stimuli and ensembles with no distinctive background. Finally, topographic artificial neural networks implementing architectural constraints meant to capture OTC spatial organization similarly exhibited two dissociable clusters of food-selective units based on sensitivity to ensemble statistics. Together, these findings suggest that lateral food representations reflect action-relevant properties shared with other manipulable objects, whereas ventral food representations arise from surface-based visual features critical for food identification.

Interactions with the environment follow stable spatial regularities that allow the brain to predict where sensory events are likely to occur. Although these expectations can adapt when actions repeatedly produce altered sensory consequences, whether spatial regularities learned through action influence subsequent sensory processing in the absence of action remains unclear. Participants underwent virtual reality (VR) sensorimotor remapping training in which right-hand interactions produced tactile feedback on either the ipsilateral (n=23) or contralateral foot (n=23). Feedback was either synchronous with hand object contact, establishing a reliable action sensation relationship, or asynchronous, providing comparable tactile exposure without a consistent temporal contingency. Before and after training, EEG was recorded during a visuo-tactile looming task in which participants passively observed objects approaching the hand while tactile stimulation was delivered to the hand (expected) or occasionally to the foot (unexpected). We examined the mismatch negativity (MMN) and P300 to determine whether the learned hand-to-foot regularity influenced subsequent processing of these events. P300 responses to hand stimulation increased selectively following synchronous training, indicating that learning a reliable hand-to-foot relationship altered subsequent processing of hand-related events outside the action context. In contrast, neither MMN nor P300 responses to foot stimulation differed between synchronous and asynchronous training, providing no evidence for direct transfer of the newly learned spatial mapping. Relative to baseline, foot-related responses instead showed contingency independent changes consistent with more general exposure related adaptation. Together, these findings show that spatial regularities learned through action can influence subsequent sensory processing beyond the context in which they are acquired, while highlighting constraints on their generalization across active and passive interactions.

Flexible behavior requires persistence when a strategy remains effective and rapid updating when its consequences change. Melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus regulate feeding, reward and memory, but their contribution to reward guided flexibility is unknown. Here, mice learned an action-outcome contingency in a T-maze and then adapted when the reward location switched. MCHR1 antagonism throughout learning did not measurably alter Initial Learning but reduced perseverative choices and accelerated behavioral adaptation after the contingency switched. Endogenous LH-MCH activity was strongest while contingencies were being established or revised, declined as performance stabilized, distinguished rewarded from unrewarded outcomes, and reflected current outcomes in the context of recent and accumulated experience. MCHR1 blockade altered prelimbic responses to successful outcomes in both phases and opposed their progressive weakening during Rule Switch. Together, these findings identify MCH signaling as a regulator of how strongly past reward continues to guide behavior when contingencies change and reveal accompanying changes in prefrontal processing of successful outcomes.

Interactions between melanin-concentrating hormone (MCH) neurons and oxytocin neurons are crucial for parental care. Whole-cell patch-clamp recordings demonstrated that MCH inhibits paraventricular hypothalamic nucleus (PVN)-oxytocin neurons through activation of barium-sensitive inwardly rectifying potassium channels, potentially G-protein coupled inwardly rectifying potassium channels, and pup-directed aggression was positively related to loss of MCH neurons. Our findings offer a glimpse into the neural mechanisms underlying the evolutionary regulation of offspring caregiving and abuse in males.