Attention is the cornerstone of effective functioning in a complex and information-rich world. While the neural activity of attention has been extensively studied in the cortex, the brain-wide neural activity patterns are largely unknown. In this study, we conducted a comprehensive analysis of neural activity across the mouse brain during attentional processing using EEG and c-Fos staining, utilizing hierarchical clustering and c-Fos-based functional network analysis to evaluate the c-Fos activation patterns. Our findings reveal that a wide range of brain regions are activated, notably in the high-order cortex, thalamus, and brain stem regions involved in advanced cognition and arousal regulation, with the central lateral nucleus of the thalamus as a strong hub, suggesting the crucial role of the thalamus in attention control. These results provide valuable insights into the neural network mechanisms underlying attention, offering a foundation for formulating functional hypotheses and conducting circuit-level testing.

Flexible behavior depends on abstract rules to generalize beyond specific instances and outcome monitoring to adjust actions. Cortical circuits are posited to read out rules from high-dimensional representations of task-relevant variables in prefrontal cortex (PFC). We instead hypothesized that converging inputs from PFC, directly or via basal ganglia (BGs), enable the thalamus to select rules. We measured activity across PFC and connected thalamic nuclei of monkeys applying rules. Abstract rule information first appeared in ventroanterior thalamus (VA)-the main thalamic hub between BG and PFC. Mediodorsal thalamus (MD) also represented rule information before PFC, persisting to help maintain activation of relevant PFC cell ensembles. MD, a major recipient of midbrain dopamine input, was the first to represent information about behavioral outcomes. A PFC-BG-thalamus model reproduced key findings, and thalamic-lesion modeling disrupted PFC rule representations. This suggests that the thalamus selects high-level cognitive information from PFC and monitors behavioral outcomes of these selections.

The perception of the sensory world in mammals requires information flow from the thalamus to the cortex. Although the first-order sensory thalamus and its surrounding nuclei are considered the major hub for feedforward thalamocortical transmission, it remains unknown whether any other thalamic input could also contribute to this transmission. We found a thalamic region, the basal region of the ventromedial nucleus of the thalamus (bVM), that sends dense, tonotopically arranged projections to auditory cortex (AuC) fields. Silencing these AuC-projecting neurons severely impaired the mouse's ability to discriminate sound frequencies. These projections exhibited strong frequency-tuning preferences that matched the cortical tonotopic map. Moreover, bVM inputs were excitatory and primarily terminated on neuron-derived neurotrophic factor-positive interneurons in cortical layer 1. Silencing these inputs significantly reduced sound-evoked responses of AuC neurons. Our results reveal a non-canonical, tonotopically arranged thalamic input to cortical layer 1 that contributes to sound processing, in parallel to the classic auditory thalamocortical pathway.

Lysergic acid diethylamide (LSD) is a classic serotonergic psychedelic that induces a profoundly altered conscious state. In conjunction with psychological support, it is currently being explored as a treatment for generalized anxiety disorder and depression. The dorsolateral prefrontal cortex (DLPFC) is a brain region that is known to be involved in mood regulation and disorders; hypofunction in the left DLPFC is associated with depression. This study investigated the role of the DLPFC in the psycho-emotional effects of LSD with functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) data of healthy human participants during the acute LSD experience. In the fMRI data, we measured the correlation between changes in resting-state functional connectivity (RSFC) of the DLPFC and post-scan subjective ratings of positive mood, emotional arousal, and ego dissolution. We found significant, positive correlations between ego dissolution and functional connectivity between the left & right DLPFC, thalamus, and a higher-order visual area, the fusiform face area (FFA). Additionally, emotional arousal was significantly associated with increased connectivity between the right DLPFC, intraparietal sulcus (IPS), and the salience network (SN). A confirmational "reverse" analysis, in which the outputs of the original RSFC analysis were used as input seeds, substantiated the role of the right DLPFC and the aforementioned regions in both ego dissolution and emotional arousal. Subsequently, we measured the effects of LSD on directed functional connectivity in MEG data that was source-localized to the input and output regions of both the original and reverse analyses. The Granger causality (GC) analysis revealed that LSD increased information flow between two nodes of the 'ego dissolution network', the thalamus and the DLPFC, in the theta band, substantiating the hypothesis that disruptions in thalamic gating underlie the experience of ego dissolution. Overall, this multimodal study elucidates a role for the DLPFC in LSD-induced states of consciousness and sheds more light on the brain basis of ego dissolution.

The mediodorsal (MD) thalamus is a critical partner for the prefrontal cortex (PFC) in cognitive control. Accumulating evidence has shown that the MD regulates task uncertainty in decision making and enhance cognitive flexibility. However, the computational mechanism of this cognitive process remains unclear. Here we trained biologically-constrained computational models to delineate the mechanistic role of MD in context-dependent decision making. We show that the addition of a feedforward MD structure to the recurrent PFC increases robustness to low cueing signal-to-noise ratio, enhances working memory, and enables rapid context switching. Incorporating genetically identified thalamocortical connectivity and interneuron cell types into the model replicates key neurophysiological findings in task-performing animals. Our model reveals computational mechanisms and geometric interpretations of MD in regulating cue uncertainty and context switching to enable cognitive flexibility. Our model makes experimentally testable predictions linking cognitive deficits with disrupted thalamocortical connectivity, prefrontal excitation-inhibition imbalance and dysfunctional inhibitory cell types.

The nucleus reuniens (RE) is a midline thalamic structure interconnecting the medial prefrontal cortex (mPFC) and the hippocampus (HPC). Recent work in both rodents and humans implicates the RE in the adaptive regulation of emotional memories, including the suppression of learned fear. However, the neural correlates of aversive learning in the RE of rodents and humans remains unclear. To address this, we recorded RE activity in humans (BOLD fMRI) and rats (fiber photometry) during Pavlovian fear conditioning and extinction. In both rats and humans, we found that conditioned stimulus (CS)-evoked activity in RE reflects the associative value of the CS. In rats, we additionally found that spontaneous neural activity in RE tracks defensive freezing and shows anticipatory increases in calcium activity that precede the termination of freezing behavior. Single-unit recordings in rats confirmed that individual RE neurons index both the associative value of the CS and defensive behavior transitions. Moreover, distinct neuronal ensembles in the RE encode fear versus extinction memories. These findings suggest a conserved role of the RE across species in modulating defensive states and emotional memory processes, providing a foundation for future translational research on fear-related disorders.

Inhibition plays an important role in controlling the flow and processing of auditory information throughout the central auditory pathway, yet how inhibition shapes auditory processing in the medial geniculate body (MGB), the key region in the auditory thalamus, is poorly understood. MGB gates the flow of auditory information to the auditory cortex, and it is inhibited largely by the thalamic reticular nucleus (TRN). The TRN comprises two major classes of inhibitory neurons: parvalbumin (PV TRN )-positive and somatostatin (SST TRN )-positive neurons. PV and SST neurons have been shown to play differential roles in controlling sound responses in other brain regions. In the somatosensory and visual subregions of the TRN, PV TRN and SST TRN neurons exhibit anatomical and functional differences. However, it remains unknown whether and how PV TRN and SST TRN neurons differ in their anatomical projections from the TRN, and whether and how they differentially modulate activity in the MGB. We find that PV TRN and SST TRN neurons exhibit differential projection patterns within the thalamus: PV TRN neurons predominantly project to ventral MGB, whereas SST TRN neurons project to the dorso-medial regions of MGB. Furthermore, PV TRN and SST TRN neurons bi-directionally modulate sound responses in MGB. Selective optogenetic inactivation of PV TRN neurons increased sound-evoked activity in over a third of MGB neurons, while another large fraction of neurons showed suppressed activity. In contrast, inactivating SST TRN neurons largely reduced tone-evoked activity in MGB neurons. Cell type-specific computational models identified candidate circuit mechanisms for generating the bi-directional effects of TRN inactivation on MGB sound responses. These distinct inhibitory pathways within the auditory thalamus reveal a cell type-specific role for thalamic inhibition in auditory computation.

Animals adaptively regulate aversive memories in safe environments through extinction, a process central to exposure therapy for anxiety disorders. The limbic thalamus controls cognitive function in concert with interconnected cortical and limbic structures. Though medial prefrontal (mPFC) afferents to the limbic thalamus regulate aversive memory, the functional role of limbic thalamus efferents to mPFC is unclear. Here, we investigated the roles of thalamic nuclei, the reuniens (RE) and mediodorsal (MD) thalamus, projecting to the medial prefrontal cortex (mPFC) in aversive memory conditioning and extinction in male mice. Using retrograde tracing, we demonstrated that ventromedial PFC (vmPFC)- and dorsomedial PFC (dmPFC)-projecting neurons are topologically segregated within the RE and MD. Fiber photometry revealed that both RE→vmPFC and MD→vmPFC neurons respond to aversive stimuli. Notably, RE→vmPFC neurons develop shock-associated cue (CS+) response during aversive conditioning. During extinction, RE→vmPFC neurons exhibited a biphasic response to CS+, while MD→vmPFC neurons showed no cue-evoked activity. Neither optogenetic activation nor inactivation of these populations altered freezing behavior during extinction compared to controls. Collectively, these findings indicate that RE→vmPFC neurons encode aversive cue information during extinction but are dispensable for behavioral modulation. This study highlights the distinct contributions of limbic thalamus-PFC circuits to aversive memory processing.

Flexible behavior depends on abstract rules to generalize beyond specific instances, and outcome monitoring to adjust actions. Cortical circuits are posited to read out rules from high-dimensional representations of task-relevant variables in prefrontal cortex (PFC). We instead hypothesized that converging inputs from PFC, directly or via basal ganglia (BG), enable thalamus to select rules. We measured activity across PFC and connected thalamic nuclei of monkeys applying rules. Abstract rule information first appeared in ventroanterior thalamus (VA) - the main thalamic hub between BG and PFC. Mediodorsal thalamus (MD) also represented rule information before PFC, persisting to help maintain activation of relevant PFC cell ensembles. MD, a major recipient of midbrain dopamine input, was first to represent information about behavioral outcomes. A PFC-BG-thalamus model reproduced key findings, and thalamic-lesion modeling disrupted PFC rule representations. This suggests that thalamus selects high-level cognitive information from PFC and monitors behavioral outcomes of these selections.

Communication among neocortical areas is largely thought to be mediated by long-range synaptic interactions between cortical neurons, with the thalamus providing only an initial relay of information from the sensory periphery. Higher-order thalamic nuclei receive strong synaptic inputs from the cortex and send robust projections back to other cortical areas, providing a distinct and potentially critical route for corticocortical communication. However, the relative contributions of corticocortical and thalamocortical inputs to higher-order cortical function remain unclear. Using imaging of neurons and axon terminals in combination with optogenetic manipulations, we find that the higher-order visual thalamus of mice has a unique impact on the posterior medial visual cortex (PM). Whereas corticocortical projections from lower cortical areas convey robust visual information to PM, higher-order thalamocortical projections convey information about global arousal state. Together, these findings suggest a key role for the higher-order thalamus in providing contextual signals that may flexibly modulate cortical sensory processing.

Auditory processing in the cerebral cortex is considered to begin with thalamocortical inputs to layer 4 (L4) of the primary auditory cortex (A1). In this canonical model, A1 L4 inputs initiate a hierarchical cascade, with higher-order cortices receiving pre-processed information for the slower integration of complex sounds. Here, we identify alternative ascending pathways in mice that bypass A1 and directly reach multiple layers of the secondary auditory cortex (A2), indicating parallel activation of these areas alongside sequential information processing. We found that L6 of both A1 and A2 receive short-latency (<10 ms) sound inputs, comparable in speed to the canonical A1 L4 input but transmitted through higher-order thalamic nuclei. Additionally, A2 L4 is innervated by a caudal subdivision within the traditionally defined primary thalamus, which we now identify as belonging to the non-primary system. Notably, both thalamic regions receive projections from distinct subdivisions of the higher-order inferior colliculus, which in turn are directly innervated by cochlear nucleus neurons. These findings reveal alternative ascending pathways reaching A2 at L4 and L6 via secondary subcortical structures. Thus, higher-order auditory cortex processes both slow, pre-processed information and rapid, direct sensory inputs, enabling parallel and distributed processing of fast sensory information across cortical areas.

Objective. Deep learning tools applied to high-resolution neurophysiological data have significantly progressed, offering enhanced decoding, real-time processing, and readability for practical applications. However, the design of artificial neural networks to analyze neural activityin vivoremains a challenge, requiring a delicate balance between efficiency in low-data regimes and the interpretability of the results.Approach. To address this challenge, we introduce a novel specialized transformer architecture to analyze single-neuron spiking activity. The model is tested on multi-electrode recordings from the dorsal premotor cortex of non-human primates performing a motor inhibition task.Main results. The proposed architecture provides an early prediction of the correct movement direction, achieving accurate results no later than 230 ms after the Go signal presentation across animals. Additionally, the model can forecast whether the movement will be generated or withheld before a stop signal, unattended, is actually presented. To further understand the internal dynamics of the model, we compute the predicted correlations between time steps and between neurons at successive layers of the architecture, with the evolution of these correlations mirrors findings from previous theoretical analyses.Significance. Overall, our framework provides a comprehensive use case for the practical implementation of deep learning tools in motor control research, highlighting both the predictive capabilities and interpretability of the proposed architecture.

General anesthesia is administered to millions of individuals each year, however, the precise mechanism by which it induces unconsciousness remains unclear. While some theories suggest that anesthesia shares similarities with natural sleep, targeting sleep-promoting areas and inhibiting arousal nuclei, recent research indicates a more complex process. Emerging evidence highlights the critical role of corticothalamocortical circuits, which are involved in higher cognitive functions, in controlling arousal states and modulating transitions between different conscious states during anesthesia. The administration of general anesthetics disrupts connectivity within these circuits, resulting in a reversible state of unconsciousness. This review elucidates how anesthetics impair corticothalamocortical interactions, thereby affecting the flow of information across various cortical layers and disrupting higher-order cognitive functions while preserving basic sensory processing. Additionally, the role of the prefrontal cortex in regulating arousal through both top-down and bottom-up pathways was examined. These findings highlight the intricate interplay between the cortical and subcortical networks in maintaining and restoring consciousness under anesthesia, offering potential therapeutic targets for enhancing anesthesia management.

Cognitive processes such as action planning and decision-making require the integration of multiple sensory modalities in response to temporal cues, yet the underlying mechanism is not fully understood. Sleep has a crucial role for memory consolidation and promoting cognitive flexibility. Our aim is to identify the role of sleep in integrating different modalities to enhance cognitive flexibility and temporal task execution while identifying the specific brain regions that mediate this process. We have designed "Auditory-Gated Patience-to-Action" Task in which mice should process different auditory signals before action execution as well as analyzing the visual inputs for feedback of their action. Mice could learn the task rule and apply it only after sleeping period and could keep the performance constant across sessions. c-fos positive cells showed the involvement of prelimbic cortex (PrL) during task execution. Chemo-genetic inhibition verified that PrL is required for proper signal response and action timing. These findings emphasize that sleep and cortical activity are keys for cognitive flexibility in adapting to different modalities.

Visual experience gives rise to persistent theta oscillations in the mouse primary visual cortex (V1) that are specific to the familiar stimulus. Our recent work demonstrated the presence of these oscillations in higher visual areas (HVAs), where they are synchronized with V1 in a context-dependent manner. However, it remains unclear where these unique oscillatory dynamics originate. To investigate this, we conducted paired extracellular electrophysiological recordings in two visual thalamic nuclei (dorsal lateral geniculate nucleus [dLGN] and lateral posterior nucleus [LP]), the retrosplenial cortex (RSC), and the hippocampus (HPC). Oscillatory activity was not found in either of the thalamic nuclei, but a sparse ensemble of oscillating neurons was observed in both the RSC and HPC, similar to V1. To infer functional connectivity changes between the brain regions, we performed directed information analysis, which indicated a trend toward decreased connectivity in all V1-paired regions, with a consistent increase in V1 → V1 connections, suggesting that the oscillations appear to initiate independently within V1. Lastly, complete NMDA lesioning of the HPC did not abolish theta oscillations in V1 that emerge with familiarity. Altogether, these results suggest that (1) theta oscillations do not originate in the thalamus; (2) RSC exhibits theta oscillations, which may follow V1 given the temporal delay present; and (3) the HPC had a sparse group of neurons, with theta oscillations matching V1; however, lesioning suggests that these oscillations emerge independent of each other. Overall, our findings pave the way for future studies to determine the mechanisms by which diverse inputs and outputs shape this memory-related oscillatory activity in the brain.

Maintaining GABAergic inhibition within physiological limits in the medial prefrontal cortex (mPFC) is critical for working memory. While synaptic GABAAR typically mediate the primary component of mPFC inhibition, the role of extrasynaptic δ-GABAAR in working memory remains unclear. To investigate this, we used fiber photometry to examine the effects of δ-GABAAR in freely moving mice. Our results indicate that the loss of δ-GABAAR expression leads to learning and memory impairment. Specifically, activation of δ-GABAAR impaired learning and memory in WT mice but enhanced learning and memory in δ+/- knockout mice. Furthermore, δ-GABAAR activation increased calcium activity in the mPFC pyramidal neurons, an effect not observed in δ-Cas9-sgRNA virus-infected mice. Collectively, these findings suggest that δ-GABAAR deficiency impairs learning and memory by modulating the excitability of pyramidal neurons in the mPFC. These results delineate the functional contribution of δ-GABAAR to learning and memory, suggesting their role extends beyond the mere maintenance of information.

Making adaptive decisions in complex environments requires appropriately identifying sources of error1,2. The frontal cortex is critical for adaptive decisions, but its neurons show mixed selectivity to task features3 and their uncertainty estimates4, raising the question of how errors are attributed to their most likely causes. Here, by recording neural responses from tree shrews (Tupaia belangeri) performing a hierarchical decision task with rule reversals, we find that the mediodorsal thalamus independently represents cueing and rule uncertainty. This enables the relevant thalamic population to drive prefrontal reconfiguration following a reversal by appropriately attributing errors to an environmental change. Mechanistic dissection of behavioural switching revealed a transthalamic pathway for cingulate cortical error monitoring5,6 to reconfigure prefrontal executive control7. Overall, our work highlights a potential role for the thalamus in demixing cortical signals while providing a low-dimensional pathway for cortico-cortical communication.

The acquisition of knowledge and skills does not occur in isolation but learning experiences amalgamate within and across domains. The process through which learning can accelerate over time is referred to as learning-to-learn or meta-learning. While meta-learning can be implemented in recurrent neural networks, these networks tend to be trained with architectures that are not easily interpretable or mappable to the brain and with learning rules that are biologically implausible. Specifically, these rules have often employed backpropagation-through-time, which relies on information that is unavailable at synapses that are undergoing plasticity in the brain. Previous studies that exclusively used local information for their weight updates had a limited capacity to integrate information over long timespans and could not easily learn-to-learn. Here, we propose a novel gated memory network named RECOLLECT, which can flexibly retain or forget information by means of a single memory gate and is trained with a biologically plausible trial-and-error-learning that requires only local information. We demonstrate that RECOLLECT successfully learns to represent task-relevant information over increasingly long memory delays in a pro-/anti-saccade task, and that it learns to flush its memory at the end of a trial. Moreover, we show that RECOLLECT can learn-to-learn an effective policy on a reversal bandit task. Finally, we show that the solutions acquired by RECOLLECT resemble how animals learn similar tasks.

The ability to prioritize among input features according to relevance enables adaptive behaviors across the human lifespan. However, relevance often remains ambiguous, and such uncertainty increases demands for dynamic control. While both cognitive stability and flexibility decline during healthy ageing, it is unknown whether aging alters how uncertainty impacts perception and decision-making, and if so, via which neural mechanisms. Here, we assess uncertainty adjustment across the adult lifespan (N = 100; cross-sectional) via behavioral modeling and a theoretically informed set of EEG-, fMRI-, and pupil-based signatures. On the group level, older adults show a broad dampening of uncertainty adjustment relative to younger adults. At the individual level, older individuals whose modulation more closely resembled that of younger adults also exhibit better maintenance of cognitive control. Our results highlight neural mechanisms whose maintenance plausibly enables flexible task-set, perception, and decision computations across the adult lifespan.

Many anatomical and physiological features of cortical circuits, ranging from the biophysical properties of synapses to the connectivity patterns among different neuron types, exhibit consistent variation along the hierarchical axis from sensory to association areas. Notably, the temporal correlation of neural activity at rest, known as the intrinsic timescale, increases systematically along this hierarchy in both primates and rodents, analogous to the increasing scale and complexity of spatial receptive fields. However, how the timescales for task-related activity vary across brain regions and whether their hierarchical organization appears consistently across different mammalian species remain unexplored. Here, we show that both the intrinsic timescale and those of task-related activity follow a similar hierarchical gradient in the cortices of monkeys, rats, and mice. We also found that these timescales covary similarly in both the cortex and basal ganglia, whereas the timescales of thalamic activity are shorter than cortical timescales and do not conform to the hierarchical order predicted by their cortical projections. These results suggest that the hierarchical gradient of cortical timescales might represent a universal feature of intracortical circuits in the mammalian brain.

The thalamus is crucial for supporting various cognitive behaviors due to its extensive connectivity with multiple cortical regions. However, the role of the thalamus and its functional connections with cortical regions in cognitive reasoning remains unclear, since previous research has mainly focused on cortical regions when studying the neural mechanisms underlying cognitive reasoning. To fill this knowledge gap, we utilized 7 T functional magnetic resonance imaging (fMRI) to study the activation patterns of the thalamus and its functional connections with cortical regions during cognitive reasoning task, while also examining how the complexity of reasoning tasks affects thalamic activation and functional connections with cortical regions. Our findings showed that cognitive reasoning processes are related to increased activation of the thalamus and its functional connections with a specific set of cortical regions, consisting of dorsolateral prefrontal cortex, inferior frontal sulcus, intraparietal sulcus, anterior cingulate cortex/presupplementary motor area, precuneus, and ventral medial prefrontal cortex. Moreover, the increase in relational complexity of the reasoning tasks led to a corresponding increase in thalamic activation and functional connectivity with cortical regions. Given the complex thalamus structure, including multiple distinct nuclei exhibiting specific functional connections with particular cortical regions, we used an atlas defined thalamic subdivisions based on its structural connectivity with different cortical regions. Our findings indicated that these different thalamic subregions not only exhibited distinct connectivity patterns with specific cortical regions during performance of cognitive reasoning, but also showed distinct connectivity patterns varied with task complexity. Overall, our study presents evidence of the thalamus's role and its connections with cortical regions in supporting increasingly complex cognitive reasoning behavior, illuminating its contribution to higher-order cognitive functions, such as reasoning.

Cognitive flexibility relies on hierarchically structured task representations that organize task contexts, relevant environmental features, and subordinate decisions. Despite ongoing interest in the human thalamus, its role in cognitive control has been understudied. This study explored thalamic representation and thalamocortical interactions that contribute to hierarchical cognitive control in humans. We found that several thalamic nuclei, including the anterior, mediodorsal, ventrolateral, and pulvinar nuclei, exhibited stronger evoked responses when subjects switch between task contexts. Decoding analysis revealed that thalamic activity encodes task contexts within the hierarchical task representations. To determine how thalamocortical interactions contribute to task representations, we developed a thalamocortical functional interaction model to predict task-related cortical representation. This data-driven model outperformed comparison models, particularly in predicting activity patterns in cortical regions that encode context representations. Collectively, our findings highlight the significant contribution of thalamic activity and thalamocortical interactions for contextually guided hierarchical cognitive control.

Persistent, memorandum-specific neuronal spiking activity has long been hypothesized to underlie working memory1,2. However, emerging evidence suggests a potential role for 'activity-silent' synaptic mechanisms3-5. This issue remains controversial because evidence for either view has largely relied either on datasets that fail to capture single-trial population dynamics or on indirect measures of neuronal spiking. We addressed this controversy by examining the dynamics of mnemonic information on single trials obtained from large, local populations of lateral prefrontal neurons recorded simultaneously in monkeys performing a working memory task. Here we show that mnemonic information does not persist in the spiking activity of neuronal populations during memory delays, but instead alternates between coordinated 'On' and 'Off' states. At the level of single neurons, Off states are driven by both a loss of selectivity for memoranda and a return of firing rates to spontaneous levels. Further exploiting the large-scale recordings used here, we show that mnemonic information is available in the patterns of functional connections among neuronal ensembles during Off states. Our results suggest that intermittent periods of memorandum-specific spiking coexist with synaptic mechanisms to support working memory.

Executive dysfunction is a prominent feature of schizophrenia and may drive core symptoms. Dorsolateral prefrontal cortex (dlPFC) deficits have been linked to schizophrenia executive dysfunction, but mechanistic details critical for treatment development remain unclear. Here, capitalizing on recent animal circuit studies, we develop a task predicted to engage human dlPFC and its interactions with the mediodorsal thalamus (MD). We find that individuals with schizophrenia exhibit selective performance deficits when attention is guided by conflicting cues. Task performance correlates with lateralized MD-dlPFC functional connectivity, identifying a neural readout that predicts susceptibility to conflict during working memory in a larger independent schizophrenia cohort. In healthy subjects performing a probabilistic reversal task, this MD-dlPFC network predicts switching behavior. Overall, our three independent experiments introduce putative biomarkers for executive function in schizophrenia and highlight animal circuit studies as inspiration for the development of clinically relevant readouts.

Spatially heterogeneous synapse loss is a characteristic of many psychiatric and neurological disorders, but the underlying mechanisms are unclear. Here, we show that spatially-restricted complement activation mediates stress-induced heterogeneous microglia activation and synapse loss localized to the upper layers of the medial prefrontal cortex (mPFC) in male mice. Single cell RNA sequencing also reveals a stress-associated microglia state marked by high expression of the apolipoprotein E gene (Apoehigh) localized to the upper layers of the mPFC. Mice lacking complement component C3 are protected from stress-induced layer-specific synapse loss, and the Apoehigh microglia population is markedly reduced in the mPFC of these mice. Furthermore, C3 knockout mice are also resilient to stress-induced anhedonia and working memory behavioral deficits. Our findings suggest that region-specific complement and microglia activation can contribute to the disease-specific spatially restricted patterns of synapse loss and clinical symptoms found in many brain diseases.

The orbitofrontal cortex (ORB), a region crucial for stimulus-reward association, decision-making, and flexible behaviors, extensively connects with other brain areas. However, brain-wide inputs to projection-defined ORB neurons and the distribution of inhibitory neurons postsynaptic to neurons in specific ORB subregions remain poorly characterized. Here we mapped the inputs of five types of projection-specific ORB neurons and ORB outputs to two types of inhibitory neurons. We found that different projection-defined ORB neurons received inputs from similar cortical and thalamic regions, albeit with quantitative variations, particularly in somatomotor areas and medial groups of the dorsal thalamus. By counting parvalbumin (PV) or somatostatin (SST) interneurons innervated by neurons in specific ORB subregions, we found a higher fraction of PV neurons in sensory cortices and a higher fraction of SST neurons in subcortical regions targeted by medial ORB neurons. These results provide insights into understanding and investigating the function of specific ORB neurons.

Tinnitus has been identified as a potential contributor to anxiety. Thalamo-cortical pathway plays a crucial role in the transmission of auditory and emotional information, but its casual link to tinnitus-associated anxiety remains unclear. In this study, we explore the neural activities in the thalamus and cortex of the sodium salicylate (NaSal)-treated mice, which exhibit both hyperacusis and anxiety-like behaviors. We find an increase in gamma band oscillations (GBO) in both auditory cortex (AC) and prefrontal cortex (PFC), as well as phase-locking between cortical GBO and thalamic neural activity. These changes are attributable to a suppression of GABAergic neuron activity in thalamic reticular nucleus (TRN), and optogenetic activation of TRN reduces NaSal-induced hyperacusis and anxiety-like behaviors. The elevation of endocannabinoid (eCB)/ cannabinoid receptor 1 (CB1R) transmission in TRN contributes to the NaSal-induced abnormalities. Our results highlight the regulative role of TRN in the auditory and limbic thalamic-cortical pathways.

Alzheimer's disease (AD) is a complex neurodegenerative condition that causes a range of cognitive disturbances, including mirror-self misidentification syndrome (MSM), in which patients cannot recognize themselves in a mirror. However, the mechanism of action of MSM is not precisely known. This study aimed to explore the possible neural mechanisms of action of MSM in AD using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).

This study included 48 AD patients, 13 in the MSM group and 35 in the non-MSM group. The permeability of the blood-brain barrier (BBB) was quantitatively monitored by measuring the transfer rate (Ktrans) of the contrast agent from the vasculature to the surrounding tissue using DCE-MRI. The concentration of contrast agents in different brain regions was measured, and the Patlak model was used to calculate Ktrans. Ktrans values were compared between the left and right cerebral hemispheres in different brain areas between the MSM and non-MSM groups. Additionally, the difference in Ktrans values between mild and severe MSM was assessed. Logistic regression analysis was used to examine the risk factors for MSM.

The Mann‒Whitney U test was used to compare two groups and revealed elevated Ktrans values in the left thalamus, left putamen, left globus pallidus, left corona radiata, and right caudate in the MSM group (p < 0.05). Logistic regression analysis revealed that increased Ktrans values in the left putamen (OR = 1.53, 95% CI = 1.04, 2.26) and left globus pallidus (OR = 1.54, 95% CI = 1.02, 2.31) may be risk factors for MSM. After dividing MSM patients into mild and moderate-severe groups, the Ktrans values of the thalamus in the moderate-severe group were greater than those in the mild group (p < 0.05).

Our study revealed the relationship between BBB permeability and MSM in AD. MSM is associated with BBB breakdown in the left putamen and globus pallidus. The left putamen and globus pallidus may function in mirror self-recognition. Higher BBB permeability in the thalamus may reflect the severity of AD in MSM.

The medial prefrontal cortex [cingulate region (Brodmann, 1909) (CNG)] in the rat is a connectionally and functionally diverse structure. It harbors cerebral nuclei that use long-range connections to promote adaptive changes to ongoing behaviors. The CNG is often described across functional and anatomical gradients, a dorsalventral gradient being the most prominent. Topographic organization is a general feature of the nervous system, and it is becoming clear that such spatial arrangements can reflect connectional, functional, and cellular differences. Portions of the CNG are known to form reciprocal connections with cortical areas and thalamus; however, these connectional features have not been described in detail or mapped to standardized rat brain atlases. Here, we used co-injected anterograde (Phaseolus vulgaris leucoagglutinin) and retrograde (cholera toxin B subunit) tracers throughout the CNG to identify zones of reciprocal connectivity in the diencephalon [or interbrain (Baer, 1837) (IB)]. Tracer distributions were observed using a Nissl-based atlas-mapping approach that facilitates description of topographic organization. This draft report describes CNG connections of the infralimbic area (Rose & Woolsey, 1948) (ILA) and the anterior cingulate area, dorsal part (Krettek & Price, 1977) (ACAd) throughout the IB. We found that corticothalamic connections are predominantly reciprocal, and that ILA and ACAd connections tended to be spatially segregated with minimal overlap. In the hypothalamus (Kuhlenbeck, 1927), we found dense and specific ILA-originating terminals in the following Brain Maps 4.0 atlas territories: dorsal region (Swanson, 2004) (LHAd) and suprafornical region (Swanson, 2004) (LHAs) of the lateral hypothalamic area (Nissl, 1913), parasubthalamic nucleus (Wang & Zhang, 1995) (PSTN), tuberal nucleus, terete part (Petrovich et al., 2001) (TUte), and an ill-defined dorsal cap of the medial mammillary nucleus (Gudden, 1881) (MM). We discuss these findings in the context of feeding behaviors.

Cognitive flexibility is a fundamental ability that enables humans and animals to exhibit appropriate behaviors in various contexts. The thalamocortical interactions between the prefrontal cortex (PFC) and the mediodorsal thalamus (MD) have been identified as crucial for inferring temporal context, a critical component of cognitive flexibility. However, the neural mechanism responsible for context inference remains unknown. To address this issue, we propose a PFC-MD neural circuit model that utilizes a Hebbian plasticity rule to support rapid, online context inference. Specifically, the model MD thalamus can infer temporal contexts from prefrontal inputs within a few trials. This is achieved through the use of PFC-to-MD synaptic plasticity with pre-synaptic traces and adaptive thresholding, along with winner-take-all normalization in the MD. Furthermore, our model thalamus gates context-irrelevant neurons in the PFC, thus facilitating continual learning. We evaluate our model performance by having it sequentially learn various cognitive tasks. Incorporating an MD-like component alleviates catastrophic forgetting of previously learned contexts and demonstrates the transfer of knowledge to future contexts. Our work provides insight into how biological properties of thalamocortical circuits can be leveraged to achieve rapid context inference and continual learning.

The microcircuitry within superficial layers of the dorsolateral prefrontal cortex (DLPFC), composed of excitatory pyramidal neurons and inhibitory GABAergic interneurons, has been suggested as the neural substrate of working memory performance. In schizophrenia, working memory impairments are thought to result from alterations of microcircuitry within the DLPFC. GABAergic interneurons, in particular, are crucially involved in synchronizing neural activity at gamma frequency, the power of which increases with working memory load. Alterations of GABAergic interneurons, particularly parvalbumin (PV) and somatostatin (SST) subtypes, are frequently observed in schizophrenia. Abnormalities of GABAergic neurotransmission, such as deficiencies in the 67 kDA isoform of GABA synthesis enzyme (GAD67), vesicular GABA transporter (vGAT), and GABA reuptake transporter 1 (GAT1) in presynaptic boutons, as well as postsynaptic alterations in GABA A receptor subunits further contribute to impaired inhibition. This review explores GABAergic abnormalities of the postmortem DLPFC in schizophrenia, with a focus on the roles of interneuron subtypes involved in cognition, and GABAergic neurotransmission within presynaptic boutons and postsynaptic alterations. Where available, comparisons between schizophrenia and affective disorders that share cognitive pathology such as bipolar disorder and major depressive disorder will be made. Challenges in directly measuring GABA levels are addressed, emphasizing the need for innovative techniques. Understanding GABAergic abnormalities and their implications for neural circuit dysfunction in schizophrenia is crucial for developing targeted therapies.

Cognitive flexibility relies on hierarchically structured task representations that organize task contexts, relevant environmental features, and subordinate decisions. Despite ongoing interest in the human thalamus, its role in cognitive control has been understudied. This study explored thalamic representation and thalamocortical interactions that contribute to hierarchical cognitive control in humans. We found that several thalamic nuclei, including the anterior, mediodorsal, ventrolateral, and pulvinar nuclei, exhibited stronger evoked responses when subjects switch between task contexts. Decoding analysis revealed that thalamic activity encodes task contexts within the hierarchical task representations. To determine how thalamocortical interactions contribute to task representations, we developed a thalamocortical functional interaction model to predict task-related cortical representation. This data-driven model outperformed comparison models, particularly in predicting activity patterns in cortical regions that encode context representations. Collectively, our findings highlight the significant contribution of thalamic activity and thalamocortical interactions for contextually guided hierarchical cognitive control.

The medial prefrontal cortex (mPFC) has been proposed to link sensory inputs and behavioral outputs to mediate the execution of learned behaviors. However, how such a link is implemented has remained unclear. To measure prefrontal neural correlates of sensory stimuli and learned behaviors, we performed population calcium imaging during a new tone-signaled active avoidance paradigm in mice. We developed an analysis approach based on dimensionality reduction and decoding that allowed us to identify interpretable task-related population activity patterns. While a large fraction of tone-evoked activity was not informative about behavior execution, we identified an activity pattern that was predictive of tone-induced avoidance actions and did not occur for spontaneous actions with similar motion kinematics. Moreover, this avoidance-specific activity differed between distinct avoidance actions learned in two consecutive tasks. Overall, our results are consistent with a model in which mPFC contributes to the selection of goal-directed actions by transforming sensory inputs into specific behavioral outputs through distributed population-level computations.

Thalamus function and structure are known predictors of individual differences in the risk of age-related neurocognitive disorders (NCD), such as dementia. However, to date, little is known about their role in the perioperative setting. Here, we provide a narrative review of brain-imaging studies of preoperative and postoperative thalamus scanning parameters associated with risks of developing perioperative NCD, such as postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) during the postoperative phase. These findings are discussed in light of the concept of reserve capacity.

Thalamic abnormalities have been repeatedly implicated in the pathophysiology of schizophrenia and other neurodevelopmental disorders. Uncovering the etiology of thalamic abnormalities and how they may contribute to illness phenotypes faces at least two obstacles. First, the typical developmental trajectories of thalamic nuclei and their association with cognition across the lifespan are largely unknown. Second, modest effect sizes indicate marked individual differences and pose a significant challenge to personalized medicine. To address these knowledge gaps, we characterized the development of thalamic nuclei volumes using normative models generated from the Human Connectome Project Lifespan datasets (5-100+ years), then applied them to an independent clinical cohort to determine the frequency of thalamic volume deviations in people with schizophrenia (17-61 years). Normative models revealed diverse non-linear age effects across the lifespan. Association nuclei exhibited negative age effects during youth but stabilized in adulthood until turning negative again with older age. Sensorimotor nuclei volumes remained relatively stable through youth and adulthood until also turning negative with older age. Up to 18% of individuals with schizophrenia exhibited abnormally small (i.e., below the 5th centile) mediodorsal and pulvinar volumes, and the degree of deviation, but not raw volumes, correlated with the severity of cognitive impairment. While case-control differences are robust, only a minority of patients demonstrate unusually small thalamic nuclei volumes. Normative modeling enables the identification of these individuals, which is a necessary step toward precision medicine.

Current concepts of corticothalamic organization in the mammalian brain are mainly based on sensory systems, with less focus on circuits for higher-order cognitive functions. In sensory systems, first-order thalamic relays are driven by subcortical inputs and modulated by cortical feedback, while higher-order relays receive strong excitatory cortical inputs. The applicability of these principles beyond sensory systems is uncertain. We investigated mouse prefronto-thalamic projections to the midline thalamus, revealing distinct top-down control. Unlike sensory systems, this pathway relies on indirect modulation via the thalamic reticular nucleus (TRN). Specifically, the prelimbic area, which influences emotional and motivated behaviors, impacts instrumental avoidance responses through direct and indirect projections to the paraventricular thalamus. Both pathways promote defensive states, but the indirect pathway via the TRN is essential for organizing avoidance decisions through disinhibition. Our findings highlight intra-thalamic circuit dynamics that integrate cortical cognitive signals and their role in shaping complex behaviors.

Cognitive and behavioral rigidity are observed in various psychiatric diseases, including in autism spectrum disorder (ASD). However, the underlying mechanism remains to be elucidated. In this study, we found that neuroligin-3 (NL3) R451C knockin mouse model of autism (KI mice) exhibited deficits in behavioral flexibility in choice selection tasks. Single-unit recording of medium spiny neuron (MSN) activity in the nucleus accumbens (NAc) revealed altered encoding of decision-related cue and impaired updating of choice anticipation in KI mice. Additionally, fiber photometry demonstrated significant disruption in dynamic mesolimbic dopamine (DA) signaling for reward prediction errors (RPEs), along with reduced activity in medial prefrontal cortex (mPFC) neurons projecting to the NAc in KI mice. Interestingly, NL3 re-expression in the mPFC, but not in the NAc, rescued the deficit of flexible behaviors and simultaneously restored NAc-MSN encoding, DA dynamics, and mPFC-NAc output in KI mice. Taken together, this study reveals the frontostriatal circuit dysfunction underlying cognitive inflexibility and establishes a critical role of the mPFC NL3 deficiency in this deficit in KI mice. Therefore, these findings provide new insights into the mechanisms of cognitive and behavioral inflexibility and potential intervention strategies.

The brain exhibits a remarkable ability to learn and execute context-appropriate behaviors. How it achieves such flexibility, without sacrificing learning efficiency, is an important open question. Neuroscience, psychology, and engineering suggest that reusing and repurposing computations are part of the answer. Here, we review evidence that thalamocortical architectures may have evolved to facilitate these objectives of flexibility and efficiency by coordinating distributed computations. Recent work suggests that distributed prefrontal cortical networks compute with flexible codes, and that the mediodorsal thalamus provides regularization to promote efficient reuse. Thalamocortical interactions resemble hierarchical Bayesian computations, and their network implementation can be related to existing gating, synchronization, and hub theories of thalamic function. By reviewing recent findings and providing a novel synthesis, we highlight key research horizons integrating computation, cognition, and systems neuroscience.

Functional interactions between the prefrontal cortex and hippocampus, as revealed by strong oscillatory synchronization in the theta (6-11 Hz) frequency range, correlate with memory-guided decision-making. However, the degree to which this form of long-range synchronization influences memory-guided choice remains unclear. We developed a brain-machine interface that initiated task trials based on the magnitude of prefrontal-hippocampal theta synchronization, then measured choice outcomes. Trials initiated based on strong prefrontal-hippocampal theta synchrony were more likely to be correct compared to control trials on both working memory-dependent and -independent tasks. Prefrontal-thalamic neural interactions increased with prefrontal-hippocampal synchrony and optogenetic activation of the ventral midline thalamus primarily entrained prefrontal theta rhythms, but dynamically modulated synchrony. Together, our results show that prefrontal-hippocampal theta synchronization leads to a higher probability of a correct choice and strengthens prefrontal-thalamic dialogue. Our findings reveal new insights into the neural circuit dynamics underlying memory-guided choices and highlight a promising technique to potentiate cognitive processes or behavior via brain-machine interfacing.

Severe traumatic brain injuries typically result in loss of consciousness or coma. In deeply comatose patients with traumatic brain injury, cortical dynamics become simple, repetitive, and predictable. We review evidence that this low-complexity, high-predictability state results from a passive cortical state, represented by a stable repetitive attractor, that hinders the flexible formation of neuronal ensembles necessary for conscious experience. Our data and those from other groups support the hypothesis that this cortical passive state is because of the loss of thalamocortical input. We identify the unpredictability and complexity of cortical dynamics captured by local field potential as a sign of recovery from this passive coma attractor. In this Perspective article, we discuss how these electrophysiological biomarkers of the recovery of consciousness could inform the design of closed-loop stimulation paradigms to treat disorders of consciousness.

The lateral amygdala (LA) encodes fear memories by potentiating sensory inputs associated with threats and, in the process, recruits 10-30% of its neurons per fear memory engram. However, how the local network within the LA processes this information and whether it also plays a role in storing it are still largely unknown. Here, using ex vivo 12-patch-clamp and in vivo 32-electrode electrophysiological recordings in the LA of fear-conditioned rats, in combination with activity-dependent fluorescent and optogenetic tagging and recall, we identified a sparsely connected network between principal LA neurons that is organized in clusters. Fear conditioning specifically causes potentiation of synaptic connections between learning-recruited neurons. These findings of synaptic plasticity in an autoassociative excitatory network of the LA may suggest a basic principle through which a small number of pyramidal neurons could encode a large number of memories.