Measuring synaptic efficacy and defining the rules for induction of synaptic plasticity at identified connections in the mammalian brain is essential for understanding how synapses contribute to learning and memory. This requires new approaches to selectively evoke presynaptic activity and measure postsynaptic responses with high spatiotemporal resolution and high sensitivity over long periods in vivo. Here we develop an all-optical approach to probe synaptic plasticity at identified cerebellar synapses in awake, behaving mice. We developed and applied JEDI-2Psub, a genetically encoded voltage indicator with increased sensitivity around resting membrane potentials, to record subthreshold and suprathreshold activity in Purkinje cell (PC) dendrites while selectively activating their granule cell (GrC) inputs using optogenetics and their climbing fiber (CF) inputs using sensory stimulation. We measured synaptic potentials and complex spike signals across the dendrites of multiple neighboring PCs, enabling us to examine correlations in voltage signals within and between neurons. We show how pairing GrC activity with sensory-evoked CF inputs can trigger long-term plasticity of inhibitory responses in PCs. These results provide a blueprint for defining the rules for plasticity induction at identified synapses in awake animals during behavior.

Episodic memories are initially encoded in the hippocampus and subsequently undergo systems consolidation into the neocortex. The nature of memories stored in the hippocampus and neocortex differs, with the cortex encoding memories in more generalized forms. Although several brain regions encode social information, the specific cortical regions and circuits involved in the consolidation of social memories and the nature of the information encoded in the cortex remain unclear. Using in vivo Ca imaging and optogenetic manipulations, we found that infralimbic (IL) neurons projecting to the nucleus accumbens shell (IL) store consolidated social memories in male mice. Inactivating IL neurons that responded to a familiar conspecific impaired the recognition of other familiar mice including littermates, demonstrating that these neuronal activities support social familiarity. Furthermore, inactivating hippocampal ventral CA1 neurons projecting to the IL region disrupted the consolidation of memory for newly familiarized mice while sparing the recognition of littermates. These findings demonstrate the critical role of hippocampal-cortical interactions in the consolidation of social memory.

Every explored environment is represented in the hippocampus by the activity of distinct populations of pyramidal cells (PCs) that typically fire at specific locations called their place fields (PFs). New PFs are constantly born even in familiar surroundings (during representational drift), and many rapidly emerge when the animal explores a new or altered environment (during global or partial remapping). Behavioral time scale synaptic plasticity (BTSP), a plasticity mechanism based on prolonged somatic action potential (AP) bursts induced by dendritic Ca/NMDA plateau potentials, was recently proposed as the main cellular mechanism underlying new PF formations (PFFs), but it is unclear whether burst-associated large somatic [Ca] transients are always necessary and/or sufficient for PFF. To address this issue, here we performed in vivo two-photon [Ca] imaging of hippocampal CA1 PCs in head-restrained mice to investigate somatic [Ca] dynamics underlying PFFs in familiar and novel virtual environments. Our results demonstrate that although many PFs are formed by BTSP-like events, PFs also emerge with initial [Ca] dynamics that do not match any of the characteristics of BTSP. BTSP- and non-BTSP-like new PFFs occur spontaneously in familiar environments, during neuronal representational switches, and instantaneously in new environments. Our data also reveal that solitary [Ca] transients with larger amplitudes than those evoking BTSP-like PFFs frequently occur without inducing PFs, demonstrating that large [Ca] transients per se are not sufficient for PFF.

Sleep entails profound changes in the brain and body, marked by altered states of consciousness and reduced somatic and autonomic motor activity. Regarding "how" sleep is regulated, whole-brain screening revealed large sleep-control networks spanning the forebrain, midbrain, and hindbrain. We unify diverse experimental evidence under a "motor theory," in which the sleep-control mechanism is integral to somatic and autonomic motor circuits. Regarding the "why" question, sleep deprivation impairs cognition, emotion, metabolism, and immunity. We propose catecholamine (dopamine, noradrenaline, and adrenaline) inactivation as the fundamental biological process underlying sleep's numerous benefits. Beyond brain arousal and motor activity, catecholamines regulate metabolism and immunity; their sleep-dependent suppression yields wide-ranging advantages, promoting repair and rejuvenation. Furthermore, catecholaminergic neurons are metabolically vulnerable; their need for rest and recovery may drive homeostatic sleep pressure. Together, the motor theory offers a unifying framework for sleep control, while the catecholamine hypothesis posits a core mechanism mediating sleep's multifaceted benefits.

Dopaminergic neurons (DANs) in the substantia nigra pars lateralis (SNL) project to the tail of striatum, where they contribute to threat behaviors. Auditory cortex contributes to threat conditioning, but whether it directly modulates DANs is unclear. Here, we show that SNL DANs fire irregularly, achieve rapid maximal firing rates, exhibit distinct ionic conductances, and receive predominantly excitatory input. This contrasts with substantia nigra pars compacta (SNc) DANs that fire regularly and receive mainly inhibitory input, establishing SNL DANs as a physiologically distinct dopaminergic subpopulation. Functional mapping revealed robust excitatory input from auditory and temporal association cortices to SNL DANs, but not SNc DANs. In behavioral experiments, inhibiting neurotransmitter release from either SNL DANs or cortical afferents to SNL resulted in impaired auditory threat conditioning. Thus, our work reveals robust functional corticonigral projections to SNL DANs which directly regulate threat behaviors.

Dopamine midbrain (DA) neurons are involved in a wide array of key brain functions including movement control and reward-based learning. They are also critical for major brain disorders such as Parkinson Disease or schizophrenia. DA neurons projecting to distinct striatal territories are diverse with regards to their molecular makeup and cellular physiology, which are likely to contribute to the observed differences in temporal dopamine dynamics. Among these regions, the dorsolateral striatum (DLS) displays the fastest dopamine dynamics, which might control the moment-to-moment vigor and variability of voluntary movements. However, the underlying mechanisms for these DLS-specific fast DA fluctuations are unresolved. Here, we show that DLS-projecting DA neurons in the substantia nigra (SN) possess a unique biophysical profile allowing immediate 10-fold accelerations in discharge frequency via rebound bursting. By using a combination of patch-clamp recordings in projection-defined DA SN subpopulations from adult male mice and developing matching projection-specific computational models, we demonstrate that a strong interaction of Ca3 and SK channels specific for DLS-projecting Aldh1a1-positive DA SN (DLS-DA) neurons controls the gain of fast rebound bursting, while K4 and HCN channels mediate timing of rebound excitability. In addition, GIRK channels activated by D2- and GABA-receptors prevent rebound bursting in these DLS-DA neurons. Furthermore, our in vivo patch-clamp recordings and matching in vivo computational models provide evidence that these unique rebound properties might be preserved in the intact brain, where they might endow specific computational properties well suited for the generation of fast dopamine dynamics present in the dorsolateral striatum. DLS-projecting DA neurons in the SN exhibit unique rebound bursting that enables rapid, 10-fold increases in firing frequency. This firing fingerprint is driven by Ca3 and SK channel interactions, modulating burst gain, and fine-tuned by K4 and HCN channels controlling rebound timing. GIRK channels, activated by D2- and GABA-receptors, inhibit this bursting. In vivo patch-clamp recordings provide evidence that these rebound dynamics might be preserved in the intact brain, potentially supporting the fast dopamine fluctuations crucial for controlling movement vigor and variability in the DLS. These findings provide insights into the mechanisms underlying fast DA dynamics and their role in motor function, with implications for brain disorders like Parkinson disease and schizophrenia.

Similar to motor skill learning in mammals, vocal learning in songbirds requires a set of interconnected brain areas that make up an analogous basal ganglia-thalamocortical circuit known as the anterior forebrain pathway (AFP). Although neural activity in the AFP has been extensively investigated during awake singing, very little is known about its neural activity patterns during other behavioral states. Here, we used chronically implanted Neuropixels probes to investigate spontaneous neural activity in the AFP during natural sleep and awake periods in male zebra finches. We found that during sleep, neuron populations in the pallial region LMAN (lateral magnocellular nucleus of the nidopallium) spontaneously exhibited synchronized bursts that were characterized by a negative sharp deflection in the local field potential (LFP) and a transient increase in gamma power. LMAN population bursts occurred primarily during non-rapid eye movement (NREM) sleep and were highly reminiscent of sharp-wave ripple (SWR) activity observed in rodent hippocampus. We also examined the functional connectivity within the AFP by calculating the pairwise LFP coherence. As expected, delta and theta band coherence within LMAN and Area X was higher during sleep compared to awake periods. Contrary to our expectations, we did not observe strong coherence between LMAN and Area X during sleep, suggesting that the input from LMAN into Area X is spatially restricted. Overall, these results provide the first description of spontaneous neural dynamics within the AFP across behavioral states. Although cortical and basal ganglia circuits are known to be required for learning in both mammals and birds, little is known about the ongoing spontaneous activity patterns within these circuits, or how they are modulated by behavioral state. Here we prove the first description of cortical-basal ganglia network activity during sleep and awake periods in birds. Within the pallial area LMAN, we observed population-wide bursting events that were highly reminiscent of hippocampal sharp-wave ripple (SWR) activity, suggesting that large-scale population events have diverse functions across vertebrates.

Spiny projection neurons (SPNs) in the dorsal striatum play crucial roles in locomotion control and value-based decision-making. SPNs, which include both direct-pathway striatonigral and indirect-pathway striatopallidal neurons, can be further classified into subtypes based on distinct transcriptomic profiles and cell body distribution patterns. However, how these SPN subtypes regulate spontaneous locomotion in the context of environmental valence remains unclear. Using Sepw1-Cre transgenic mice, which label a specific SPN subtype characterized by a patchy distribution of cell bodies in the dorsal striatum, we found that these patchy striatonigral neurons constrain motor vigor in response to valence differentials. In a modified light/dark box test, mice exhibited differential walking speeds between the light and dark zones. Genetic ablation of these patchy SPNs disrupted restful slowing in the dark zone and increased zone discrimination by speed. In vivo recordings linked the activity of these neurons to zone occupancy, speed, and deceleration, with a specific role in mediating deceleration. Furthermore, chemogenetic activation of patchy SPNs-and optical activation of striatonigral neurons in particular-reduced locomotion and attenuated speed-based zone discrimination. These findings reveal that a subtype of patchy striatonigral neurons regulates implicit walking speed selection based on innate valence differentials.

Audiovisual working memory (WM) plays a critical role in multisensory cognitive processing, yet its structural neural correlates remain insufficiently understood. This study employed an audiovisual dual n-back task paradigm and voxel-based morphometry (VBM) to investigate gray matter volume (GMV) associations with behavioral performance in 60 healthy individuals. Behavioral results revealed a significant visual dominance effect under high cognitive load: visual performance remained stable across conditions, whereas auditory performance declined. Structural analyses showed modality-specific GMV correlations. Visual performance was positively associated with GMV in the insula, posterior cingulate, hippocampus, and inferior frontal regions, while auditory performance was negatively correlated with GMV in the angular and middle occipital gyri. Notably, the left cuneus exhibited a strong positive correlation with the Δd prime difference under high load, suggesting its potential role in cross-modal resource allocation. Furthermore, cognitive overload appeared to disrupt the structure-behavior associations observed under lower load, highlighting a load-dependent dissociation within executive control and sensory integration regions. These findings underscore the distinct anatomical substrates supporting audiovisual WM and the neural basis of visual dominance, offering structural markers for targeted cognitive training and clinical intervention.

By recording large populations of neurons in flying bats, two recent studies have observed sequential activities in the hippocampus that represent ongoing spatial trajectories during movement and recently experienced trajectories during rest, analogous to 'theta sweeps' and 'replay' previously described in rodents.

It has been shown that in the CA1 region of the hippocampus, dopamine modulates memory functions by influencing spike-timing-dependent plasticity (STDP) and intrinsic neuronal properties. Although experimental findings have suggested potential mechanisms, their detailed interplay remains incompletely understood. Here, using a realistic CA1 pyramidal neuron model, we have investigated the possible effects of dopaminergic modulation on a neuron's signal integration and synaptic plasticity processes. The results suggest a physiological plausible explanation for the puzzling experimental observation that long-term potentiation (LTP) increases in spite of a reduction in the neuron's excitability, and explains why physiological dopamine levels are necessary for LTP induction. The model suggests experimentally testable predictions on which ion channel kinetic properties can modulate the interplay between synaptic plasticity and neuronal excitability, thereby identifying potential molecular targets for therapeutic intervention.

In temporal lobe epilepsy, interictal spikes (IS) - hyper-synchronous bursts of network activity - occur at high rates in between seizures. We sought to understand the influence of IS on working memory by recording hippocampal local field potentials from male epileptic mice while they performed a delayed alternation task. Interestingly, the rate of IS during behavior did not correlate with performance. Instead, we found that IS were correlated with worse performance when they were spatially non-restricted and occurred during running. In contrast, when IS were clustered at reward locations, animals tended to perform well. A machine learning decoding approach revealed that IS at reward sites were larger than IS elsewhere on the maze, and could be classified as occurring at specific reward locations. Finally, a spiking neural network model revealed that spatially clustered IS preserved hippocampal replay, while spatially dispersed IS disrupted replay by causing over-generalization. Together, these results show that the spatial specificity of IS on the maze, but not rate, correlates with working memory deficits. In people with epilepsy, the hippocampus can generate large electrical discharges in the period between seizures called interictal spikes. Previous studies have proposed that interictal spikes cause memory impairments. We use a mouse model of epilepsy and computer simulations to study how interictal spikes impact navigation to remembered rewards. We find that when interictal spikes occur uncontrollably throughout the maze memory performance is worse, and in contrast, when they are sequestered to reward locations memory performance is better. Together our results show that interictal spikes are correlated with corrupted memory depending on when and where they occur during learning.

Disinhibitory neurons throughout the mammalian cortex are powerful enhancers of circuit excitability and plasticity. The differential expression of neuropeptide receptors in disinhibitory, inhibitory, and excitatory neurons suggests that each circuit motif may be controlled by distinct neuropeptidergic systems. Here, we reveal that a bombesin-like neuropeptide, gastrin-releasing peptide (GRP), recruits disinhibitory cortical microcircuits through selective targeting and activation of vasoactive intestinal peptide (VIP)-expressing cells. Using a genetically encoded GRP sensor, optogenetic anterograde stimulation, and trans-synaptic tracing, we reveal that GRP regulates VIP cells most likely via extrasynaptic diffusion from several local and long-range sources. In vivo photometry and CRISPR-Cas9-mediated knockout of the GRP receptor (GRPR) in auditory cortex indicate that VIP cells are strongly recruited by novel sounds and aversive shocks, and GRP-GRPR signaling enhances auditory fear memories. Our data establish peptidergic recruitment of selective disinhibitory cortical microcircuits as a mechanism to regulate fear memories.

Volumetric functional imaging of transient cellular signaling and motion dynamics is often limited by hardware bandwidth and the scarcity of photons under short exposures. To overcome these challenges, we introduce squeezed light field microscopy (SLIM), a computational imaging approach that rapidly captures high-resolution three-dimensional light signals using only a single, low-format camera sensor. SLIM records over 1,000 volumes per second across a 550-µm diameter field of view and 300-µm depth, achieving 3.6-µm lateral and 6-µm axial resolution. Here we demonstrate its utility in blood cell velocimetry within the embryonic zebrafish brain and in freely moving tails undergoing high-frequency swings. Millisecond-scale temporal resolution further enables precise voltage imaging of neural membrane potentials in the leech ganglion and hippocampus of behaving mice. Together, these results establish SLIM as a versatile and robust tool for high-speed volumetric microscopy across diverse biological systems.

In vivo voltage imaging is a powerful tool for monitoring action potentials and dynamic electrical events in heterogeneous sensory neurons enabling the deciphering of rapid somatosensory information processing. Virus-driven expression of genetically encoded voltage indicator (GEVI) suffers from inconsistent expression levels and offers a limited time window for optimal voltage imaging. Here, we generated and characterized a knock-in mouse line with Pirt-driven expression of Marina, a positively tuned GEVI, in primary sensory neurons. Pirt-Marina mice enable optical reporting of touch, itch, and nociceptive sensations in vivo and distinct action potential patterns in the trigeminal and dorsal root ganglion neurons. Notably, Pirt-Marina mice display robust fluorescence signals in response to mechanical, thermal, or chemical stimuli, allowing visualization of transformations in sensory coding following inflammation and injury. This Pirt-Marina mouse line provides optical access to dynamic neuronal activity and plasticity in the peripheral nervous system (PNS) with high temporal accuracy, fidelity, and reliability.

A long-standing question in biology and medicine concerns how astrocytes influence neurons. Here, progress concerning how astrocytes affect neurons and neural circuits is summarized by focusing on data and concepts from studies of the striatum, which has emerged as a model nucleus. Mechanisms broadly applicable across brain regions and disorders are emphasized, and knowledge gaps are described. Experiments spanning multiple scales of biology show that astrocytes regulate neural circuits by virtue of homeostatic signaling and through astrocyte-neuron interactions. During disease, astrocytes contribute to nervous system malfunction in context-specific ways through failures of normal functions and the development of maladaptive responses. As ideally positioned endogenous cellular neuromodulators, astrocytes can be targeted for strategies to regulate neural circuits in brain disorders. After a historically slow start for the field, astrocyte-neuron interactions are now recognized as consequential for physiology and behavior, critically involved in pathophysiology, and exploitable in disease.

Every explored environment is represented in the hippocampus by the activity of distinct populations of pyramidal cells (PCs) that typically fire at specific locations called their place fields (PFs). New PFs are constantly born even in familiar surroundings (during representational drift), and many rapidly emerge when the animal explores a new or altered environment (during global or partial remapping). Behavioral time scale synaptic plasticity (BTSP), a plasticity mechanism based on prolonged somatic action potential (AP) bursts induced by dendritic Ca2+/NMDA plateau potentials, was recently proposed as the main cellular mechanism underlying new PF formations (PFF), but it is unclear whether burst-associated large somatic [Ca2+] transients are always necessary and/or sufficient for PFF. To address this issue, here we performed in vivo two-photon [Ca2+] imaging of hippocampal CA1 PCs in head-restrained mice to investigate somatic [Ca2+] dynamics underlying PFFs in familiar and novel virtual environments. Our results demonstrate that although many PFs are formed by BTSP-like events, PFs also emerge with initial [Ca2+] dynamics that do not match any of the characteristics of BTSP. BTSP and non-BTSP-like new PFFs occur spontaneously in familiar environments, during neuronal representational switches and instantaneously in new environments. Our data also reveal that solitary [Ca2+] transients with larger amplitudes than those evoking BTSP-like PFFs, frequently occur without inducing PFs, demonstrating that large [Ca2+] transients per se are not sufficient for PFF.

In the hippocampal formation, cholinergic modulation from the medial septum/diagonal band of Broca (MSDB) is known to correlate with the speed of an animal's movements at sub-second timescales and also supports spatial memory formation. Yet, the extent to which sub-second cholinergic dynamics, if at all, align with transient behavioral and cognitive states supporting the encoding of novel spatial information remains unknown. In this study, we used fiber photometry to record the temporal dynamics in the population activity of septo-hippocampal cholinergic neurons at sub-second resolution during a hippocampus-dependent object location memory task using ChAT-Cre mice of both sexes. Using a linear mixed-effects model, we quantified the extent to which cholinergic dynamics were explained by changes in movement speed, behavioral states such as locomotion, grooming, and rearing, and hippocampus-dependent cognitive states such as recognizing a novel location of a familiar object. The data show that cholinergic dynamics contain a multiplexed code of fast and slow signals i) coding for the logarithm of movement speed at sub-second timescales, ii) providing a phasic spatial novelty signal during the brief periods of exploring a novel object location, and iii) coding for recency of environmental change at a seconds-long timescale. Furthermore, behavioral event-related phasic cholinergic activity demonstrates that fast cholinergic transients correlate with a switch in cognitive and behavioral states. These findings enhance understanding of the mechanisms by which cholinergic modulation contributes to the coding of movement speed and encoding of novel spatial information. Acetylcholine is well known as a neuromodulator of cognitive functions and behavior, and computational models suggest an important role in the encoding of new memories. However, whether cholinergic dynamics are fast enough to serve as a spatial novelty signal is unknown. Here, we demonstrate that cholinergic signaling in the septo-hippocampal circuitry of mice exhibits multiple timescales of activity, where fast signals reflect the detection of novel object locations, encode the logarithm of movement speed, and correlate with behavioral state transitions. At longer timescales, cholinergic transients encode recency of environmental change. These findings provide important insights into the mechanisms by which acetylcholine contributes to encoding and retrieval dynamics and the acquisition of spatial memories during exploratory behavior and memory-guided navigation.

Traditional views of hippocampal function are largely based on the canonical flow of information from the entorhinal cortex through the trisynaptic loop-comprising the dentate gyrus and cornu ammonis regions CA3 and CA1-and back to cortex, where the hippocampus plays an important role in transforming relevant information into a usable storage system. This classic circuit has inspired current thinking on hippocampal functions related to learning, memory, and spatial navigation, but the potential functional contributions of other hippocampal areas, such as CA2, the fasciola cinereum, and the indusium griseum, and their integration of a major hypothalamic input, have been overlooked. These understudied circuits and nontraditional network dynamics such as dentate spikes have recently begun to yield fresh insights into unconventional circuit computations that extend the repertoire of hippocampal function beyond current models.

The exponential growth in academic publishing - exceeding 2 million papers annually 2023 - has rendered traditional systematic review methods unsustainable. These conventional approaches typically require 6-24 months for completion, creating critical delays between evidence availability and clinical implementation. While existing automation tools demonstrate workload reductions of 30-72.5%, their machine learning dependencies create barriers to immediate implementation. Additionally, direct AI screening methods involve substantial computational costs, lack real-time adaptability, suffer from inconsistent performance across different research domains, and provide no clear audit trail for regulatory compliance. We present a one-week systematic review acceleration protocol using rule-based automation where artificial intelligence (AI) assists with code generation. Researchers define screening criteria, then use AI language models (Claude, ChatGPT) as coding assistants. This protocol employs a two-phase screening process: (1) rule-based title/abstract screening and (2) rule-based full-text analysis, while adhering to established systematic review guidelines such as Cochrane methodology and PRISMA reporting. The rule-based system provides immediate implementation with complete transparency, while validation framework guides researchers in systematically testing screening sensitivity to minimize false negatives and ensure comprehensive study capture; meta-analysis and statistical synthesis remain manual processes requiring human expertise. We demonstrate the protocol's application through a case study examining cardiac fatty acid oxidation in heart failure with preserved ejection fraction (HFpEF), and validated through a separate review examining e-cigarette versus traditional cigarette cardiopulmonary effects, which successfully processed 3,791 records. This protocol represents a substantial advancement in systematic review methodology, making high-quality evidence synthesis more accessible across a broad range of scientific disciplines.

To report the level of knowledge, impressions, and satisfaction of Urology readers, authors, and editorial boards regarding Open Access (OA) publishing in the field of Urology and to determine their satisfaction with the current OA models.

The quality of research across psychology needs improvement. Ample evidence has indicated that publication bias, specifically making publication decisions based on a study's results, has led to a distorted literature (e.g., high rates of false positives). Registered Reports, which can now be submitted to are a recent publication format designed to combat publication bias and problematic research practices. The format represents a shift from a system in which publication decisions are based on the nature of the findings, to one that is based on the quality of the study conceptualization and design. In this invited article, we introduce the Registered Reports format to by arguing that they and be used in developmental psychopathology research. We first describe what Registered Reports are and why they are useful. We then review 10 commonly expressed concerns about publishing Registered Reports - including that they are not appropriate for studies using preexisting data, that they do not allow for exploratory analyses, and that they take too long to publish - explaining why these concerns are unwarranted. We hope that this article will allay concerns about publishing Registered Reports, and that readers will submit them to

Dynamic signaling by extracellular and intracellular molecules impacts downstream pathways in a cell-type-specific manner. Fluorescent reporters of such signals are typically optimized to detect fast, relative changes in concentration of target molecules. They are less well suited to detect slowly changing signals and rarely provide absolute measurements. Here, we developed fluorescence lifetime photometry at high temporal resolution (FLIPR), which utilizes frequency-domain analog processing to measure the absolute fluorescence lifetime of genetically encoded sensors at high speed but with long-term stability and picosecond precision. We applied FLIPR to investigate dopamine signaling in functionally distinct striatal subregions. We observed higher tonic dopamine levels in the tail of the striatum compared with the nucleus accumbens core and differential and dynamic responses in phasic and tonic dopamine to appetitive and aversive stimuli. Thus, FLIPR reports fast and slow timescale neuronal signaling in absolute units, revealing previously unappreciated spatial and temporal variation even in well-studied signaling systems.

Action control is hypothesized to be mediated by corticothalamo-basal ganglia loops subserving the acquisition and updating of action contingencies. Within this, the mediodorsal thalamus (MD) is thought to contribute to volitional control over behavior largely through its interactions with prefrontal cortex. However, MD also projects into striatum, the main input nucleus of the basal ganglia, and the contribution of such projections to behavioral control is not known. Using a mouse model of volitional action control in either sex, here we find that MD terminal calcium activity in dorsal medial striatum (MD-DMS) represents action information during initial acquisition of a novel action contingency. This representation of action information decreases with continued experience. Data demonstrate MD-DMS activity is necessary to learn and employ a contingency control over actions. Functional attenuation of MD-DMS activity negated normal exploration, instead biasing repetitive action control, and resulted in mice unable to adapt their initial action strategy upon changes in action contingency. This suggests MD supports plasticity underlying initial action strategy learning used to adjust control given changing contingencies. Overall, these data show that MD projections into striatum contribute to volitional action control that supports acquisition of adaptive behavior. Mediodorsal (MD) thalamus is hypothesized to support volitional action control. However, focus has largely been on MD input into prefrontal cortical regions and the contribution of MD input to striatum has not been explored. Here we show that MD input into dorsal medial striatum supports acquisition of goal-directed strategies and their control over actions.

The ability to form, retrieve and update autobiographical memories is one of the most fascinating features of human behavior. Spatial memory, the ability to remember the layout of the external environment and to navigate within its boundaries, is closely related to the autobiographical memory domain. It is served by an overlapping brain circuit, centered around the hippocampus (HPC) where the cognitive map index is stored. Apart from the hippocampus, several cortical structures participate in this process. Their relative contribution is a subject of intense research in both humans and animal models. One of the most widely studied regions is the retrosplenial cortex (RSC), an area in the parietal lobe densely interconnected with the hippocampal formation. Several methodological approaches have been established over decades in order to investigate the cortical aspects of memory. One of the most successful techniques is based on the analysis of brain expression patterns of the immediate early genes (IEGs). The common feature of this diverse group of genes is fast upregulation of their mRNA translation upon physiologically relevant stimulus. In the central nervous system they are rapidly triggered by neuronal activity and plasticity during learning. There is a widely accepted consensus that their expression level corresponds to the engagement of individual neurons in the formation of memory trace. Imaging of the IEGs might therefore provide a picture of an emerging memory engram. In this review we present the overview of IEG mapping studies of retrosplenial cortex in rodent models. We begin with classical techniques, immunohistochemical detection of protein and fluorescent in situ hybridization of mRNA. We then proceed to advanced methods where fluorescent genetically encoded IEG reporters are chronically followed in vivo during memory formation. We end with a combination of genetic IEG labelling and optogenetic approach, where the activity of the entire engram is manipulated. We finally present a hypothesis that attempts to unify our current state of knowledge about the function of RSC.

Gain modulation allows neurons to dynamically adjust their responsiveness to inputs without changing selectivity. While well-characterized in sensory areas, its role in higher-order brain regions governing spatial navigation and memory is unclear. Here, we used all-optical methods in mice performing a spatial task to demonstrate that vasoactive-intestinal peptide (VIP)-expressing neurons selectively control the gain of place cells and other cell types in the retrosplenial cortex (RSC) through disinhibition. Optogenetic manipulation revealed that this disinhibition, while broadly affecting network activity, selectively amplifies in-field place cell activity, improving spatial coding accuracy. In contrast, VIP neurons in the hippocampus have minimal impact on place field gain. Notably, simulations indicate that the benefit of gain modulation for RSC place cells is large compared to hippocampal place cells due to their much higher out-of-field activity and, therefore, lower signal-to-noise ratio. Here, we show an area-specific VIP-mediated gain control, enhancing spatial coding and, potentially, memory formation.

This perspective highlights new work suggesting the need for revision of the canonical direct-indirect model of the basal ganglia's influence on movement, with fresh evidence that there is a formerly unappreciated pair of direct and indirect pathways that parallel the standard model's canonical direct and indirect pathways, and promising evidence pointing toward improved clinical treatments for Parkinson's disease. As a working hypothesis, it is suggested that the non-canonical direct and indirect pathways, which arise in striosomes, might act as homeostatic circuits that can reign in or amplify the activity of the canonical pathways in the face of their imbalance, including that occurring in hyperkinetic or hypokinetic disorders. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The dorsomedial prefrontal cortex (dmPFC) and basal ganglia (BG) are tightly interconnected through cortico-BG-thalamocortical (CBGT) loops that undergo extensive refinement during postnatal development. While the role of cortical activity in shaping striatal circuit maturation is well established, the extent to which the BG regulate dmPFC development remains unclear. Here, we examined whether early striatal output influences the maturation of dmPFC activity and connectivity. Targeted ablation of direct or indirect pathway spiny projection neurons during the first two postnatal weeks induced bidirectional changes in dmPFC neural activity akin to BG modulation of cortical dynamics observed in mature circuits. Interestingly, these manipulations also disrupted synaptic maturation of layer 2/3 pyramidal neurons, shifting the balance between excitation and inhibition. Together, these findings demonstrate that striatal output regulates cortical activity during early postnatal development and suggest a previously unrecognized role for the BG in guiding the establishment of prefrontal cortical networks.

The lateral prefrontal cortex (LPFC) serves as a critical hub for higher-order cognitive and executive functions in the human brain, coordinating brain networks whose disruption has been implicated in many neurological and psychiatric disorders. While transcranial brain stimulation treatments often target the LPFC, our current understanding of connectivity profiles guiding these interventions based on electrophysiology remains limited. Here, we present a high-resolution probabilistic map of bidirectional effective connectivity between the LPFC and widespread cortical and subcortical regions. This map is derived from intracranial evoked potential analysis of 48,797 intracranial direct electrical stimulation runs across 759 implantations in 724 patients with refractory epilepsy (368 male, 354 female, two unspecified; mean age 24±13.5 years). We mapped probabilistic connectivity between brain parcels with adaptive resolution - higher resolution in the LPFC in the hemisphere of interest and lower elsewhere - maintaining statistical power while achieving 95% average confidence interval of ∼0.03 for connectivity probability estimates. In addition, the significance threshold (p-value) for probabilistic connectivity was obtained from surrogate distributions. Overall, we observed remarkable symmetry between afferent and efferent connectivity patterns of the LPFC, with a slight preference for efferent connections (mean slope = 0.92±0.09, mean R² = 0.93±0.025). For example, connections between the inferior frontal gyrus (IFG) and anterior cingulate showed notable directional asymmetry. The IFG strongly projected to most brain networks compared to other LPFC regions, with the strongest connectivity to the ventral attention network (0.26±0.01 compared to values between 0.15 and 0.21 in other LPFC regions). Posterior DLPFC demonstrated stronger connectivity to brain networks compared to anterior DLPFC regions (eg. 0.21±0.01 vs 0.15±0.01 for connectivity to ventral attention network), with the exception of the limbic cortex. All LPFC subregions strongly projected to the fronto-parietal (greater than 0.17) and ventral attention (greater than 0.15) networks, with moderate connections to the default network (between 0.1 and 0.15, with the maximum corresponding to superior DLPFC). Finally, latency analysis suggested that the left LPFC's influence on ipsilateral emotion-related regions is primarily polysynaptic, with particularly strong pathways from IFG to amygdala (0.16±0.02) and hippocampus (0.12±0.01). Taken together, these comprehensive connectivity maps provide a new detailed electrophysiological foundation for understanding the functional anatomy of LPFC and guiding targeted brain stimulation protocols.

Hippocampal place cells (PCs) are important for spatial coding and episodic memory. PCs' representations are modulated upon transitioning between environments (global remapping) but also change with repeated exposure to familiar spaces (representational drift). To gain insights into the mechanistic basis for this unique balance between circuit plasticity and stability, we used voltage imaging to longitudinally record the subthreshold and spiking activity of pyramidal neurons (PNs) and somatostatin-positive (SST) interneurons in CA1 during virtual navigation. A fraction of cells from both populations showed spatial representations, but many SSTs were speed-tuned or fired uniformly across space. Intracellular recordings revealed increased theta power and asymmetric ramp-like depolarization in PN place fields, while SSTs exhibited symmetric depolarization with no theta increase. Longitudinal recordings across weeks demonstrated representational drifts in both populations, although SSTs exhibited remarkably stable firing and subthreshold properties. Transition to a novel environment induced remapping in both populations, accompanied by increase in SST activity and reduction in PNs. These results provide new insights into how hippocampal circuits balance representational stability with experience-dependent plasticity.

Theta oscillation is considered a temporal scaffold for hippocampal computations that organizes the activity of spatially tuned cells known as place cells. Late phases of theta support prospective spatial representation via phase 'precession'. In contrast, some studies have hypothesized that early phases of theta may subserve both retrospective spatial representation via phase 'procession' and the encoding of new associations. Here, combining virtual reality, electrophysiology and computational modeling, we provide experimental evidence for such a functionally multiplexed phase code and describe how distinct spatial inputs control its manifestation. Specifically, when rats continuously learned new associations between external landmark (allothetic) cues and self-motion (idiothetic) cues, phase 'precession' remained intact, allowing continuous prediction of future positions. Conversely, phase 'procession' was diminished, matching the putative role in encoding at the early theta phase. This multiplexed phase code may serve as a general circuit logic for alternating different computations at a sub-second scale.

While cognitive function remains stable for majority of the lifespan, many functions sharply decline in later life. Women have higher rates of neurodegenerative diseases that involve memory loss, including Alzheimer's disease. This sex disparity may be due to longer life expectancies when compared to men; women outlive men by roughly 5 years globally. Despite this, most preclinical work compares aged male rodents to young adult counterparts, making it difficult to determine the relative contributions of advanced age and sex to memory function and neurodegeneration. We used male and female rats throughout old age (PND590-734) to examine the extent to which both sex and advanced age would impact trace fear memory and associated neural changes, including expression of the immediate early gene zif268, perineuronal nets (PNN) amount, and lysine-48 (K48) polyubiquitin protein tagging in brain regions necessary for trace fear memory: the prelimbic cortex (PL), the dorsal hippocampus (DH), and the basolateral amygdala (BLA). While both advanced age and biological sex impacted trace fear memory, they had no effect on acquisition or context fear retrieval. Advanced age was associated with decreased zif268 expression in the PL and DH, while biological sex had no influence. PNN amount corresponded with advanced aged in the PL, but not in the DH or BLA, and was not influenced by sex. Neither biological sex nor advanced age impacted K48 polyubiquitin levels in any region. Overall, these results suggest that advanced age has a more pronounced effect on memory impairment and associated neural changes than biological sex.

Observing the activity of large populations of neurons in vivo is critical for understanding brain function and dysfunction. The use of fluorescent genetically-encoded calcium indicators (GECIs) in conjunction with miniaturized microscopes is an exciting emerging toolset for recording neural activity in unrestrained animals. Despite their potential, current miniaturized microscope designs are limited by using image sensors with low frame rates, sensitivity, and resolution. Beyond GECIs, there are many neuroscience applications which would benefit from the use of other emerging neural indicators, such as fluorescent genetically-encoded voltage indicators (GEVIs) that have faster temporal resolution to match neuron spiking, yet, require imaging at high speeds to properly sample the activity-dependent signals. We integrated an advanced CMOS image sensor into a popular open-source miniaturized microscope platform. MiniFAST is a fast and sensitive miniaturized microscope capable of 1080p video (1920x1080 pixels), 1.5 m resolution, frame rates up to 500 Hz (achieved with windowing: 1920 x 55 pixels height) and high gain ability (up to 70 dB) to image in extremely low light conditions. We report results of ~300 Hz in vivo imaging of freely behaving transgenic Thy1-GCaMP6f mice, high speed 500 Hz in vitro imaging of a GEVI and in vivo GEVI imaging in head-fixed mice. Our results extend miniaturized microscope capabilities in high-speed imaging, high sensitivity and increased resolution, opening the door for the open-source community to use fast and dim neural indicators.