Hypothalamic-hindbrain circuit for consumption-induced fear regulation.

To ensure survival, animals must sometimes suppress fear responses triggered by potential threats during feeding. However, the mechanisms underlying this process remain poorly understood. In the current study, we demonstrated that when fear-conditioned stimuli (CS) were presented during food consumption, a neural projection from lateral hypothalamic (LH) GAD2 neurons to nucleus incertus (NI) relaxin-3 (RLN3)-expressing neurons was activated, leading to a reduction in CS-induced freezing behavior in male mice. LHGAD2 neurons established excitatory connections with the NI. The activity of this neural circuit, including NIRLN3 neurons, attenuated CS-induced freezing responses during food consumption. Additionally, the lateral mammillary nucleus (LM), which received NIRLN3 projections, along with RLN3 signaling in the LM, mediated the decrease in freezing behavior. Collectively, this study identified an LHGAD2-NIRLN3-LM circuit involved in modulating fear responses during feeding, thereby enhancing our understanding of how animals coordinate nutrient intake with threat avoidance.

The macroscale routing mechanism of structural brain connectivity related to body mass index.

Understanding the brain's mechanisms in individuals with obesity is important for managing body weight. Prior neuroimaging studies extensively investigated alterations in brain structure and function related to body mass index (BMI). However, how the network communication among the large-scale brain networks differs across BMI is underinvestigated. This study used diffusion magnetic resonance imaging of 290 young adults to identify links between BMI and brain network mechanisms. Navigation efficiency, a measure of network routing, was calculated from the structural connectivity computed using diffusion tractography. The sensory and frontoparietal networks indicated positive associations between navigation efficiency and BMI. The neurotransmitter association analysis identified that serotonergic and dopaminergic receptors, as well as opioid and norepinephrine systems, were related to BMI-related alterations in navigation efficiency. The transcriptomic analysis found that genes associated with network routing across BMI overlapped with genes enriched in excitatory and inhibitory neurons, specifically, gene enrichments related to synaptic transmission and neuron projection. Our findings suggest a valuable insight into understanding BMI-related alterations in brain network routing mechanisms and the potential underlying cellular biology, which might be used as a foundation for BMI-based weight management.

Bilateral connections from the amygdala to extrastriate visual cortex in the marmoset monkey.

It is known that the primate amygdala forms projections to many areas of the ipsilateral cortex, but the extent to which it forms connections with the contralateral visual cortex remains less understood. Based on retrograde tracer injections in marmoset monkeys, we report that the amygdala forms widespread projections to the ipsilateral extrastriate cortex, including V1 and areas in both the dorsal (MT, V4T, V3a, 19M, and PG/PFG) and the ventral (VLP and TEO) streams. In addition, contralateral projections were found to target each of the extrastriate areas, but not V1. In both hemispheres, the tracer-labeled neurons were exclusively located in the basolateral nuclear complex. The number of labeled neurons in the contralateral amygdala was small relative to the ipsilateral connection (1.2% to 5.8%). The percentage of contralateral connections increased progressively with hierarchical level. An injection in the corpus callosum demonstrated that at least some of the amygdalo-cortical connections cross through this fiber tract, in addition to the previously documented path through the anterior commissure. Our results expand knowledge of the amygdalofugal projections to the extrastriate cortex, while also revealing pathways through which visual stimuli conveying affective content can directly influence early stages of neural processing in the contralateral visual field.

iTBS reveals the roles of domain-general cognitive control and language-specific brain regions during word formation rule learning.

Repeated exposure to word forms and meanings improves lexical knowledge acquisition. However, the roles of domain-general and language-specific brain regions during this process remain unclear. To investigate this, we applied intermittent theta burst stimulation over the domain-general (group left dorsolateral prefrontal cortex) and domain-specific (Group L IFG) brain regions, with a control group receiving sham intermittent theta burst stimulation. Intermittent theta burst stimulation effects were subsequently assessed in functional magnetic resonance imaging using an artificial word learning task which consisted of 3 learning phases. A generalized psychophysiological interaction analysis explored the whole brain functional connectivity, while dynamic causal modeling estimated causal interactions in specific brain regions modulated by intermittent theta burst stimulation during repeated exposure. Compared to sham stimulation, active intermittent theta burst stimulation improved word learning performance and reduced activation of the left insula in learning phase 2. Active intermittent theta burst stimulation over the domain-general region increased whole-brain functional connectivity and modulated effective connectivity between brain regions during repeated exposure. This effect was not observed when active intermittent theta burst stimulation was applied to the language-specific region. These findings suggest that the domain-general region plays a crucial role in word formation rule learning, with intermittent theta burst stimulation enhancing whole-brain connectivity and facilitating efficient information exchange between key brain regions during new word learning.

Impact of Electric Field Magnitude in the Left Dorsolateral Prefrontal Cortex on Changes in Intrinsic Functional Connectivity Using Transcranial Direct Current Stimulation: A Randomized Crossover Study.

This study investigated whether the electric field magnitude (E-field) delivered to the left dorsolateral prefrontal cortex (L-DLPFC) changes resting-state brain activity and the L-DLPFC resting-state functional connectivity (rsFC), given the variability in tDCS response and lack of understanding of how rsFC changes. Twenty-one healthy participants received either 2 mA anodal or sham tDCS targeting the L-DLPFC for 10 min. Brain imaging was conducted before and after stimulation. The fractional amplitude of low-frequency fluctuation (fALFF), reflecting resting brain activity, and the L-DLPFC rsFC were analyzed to investigate the main effect of tDCS, main effect of time, and interaction effects. The E-field was estimated by modeling tDCS-induced individual electric fields and correlated with fALFF and L-DLPFC rsFC. Anodal tDCS increased fALFF in the left rostral middle frontal area and decreased fALFF in the midline frontal area (FWE p < 0.050), whereas sham induced no changes. Overall rsFC decreased after sham (positive and negative connectivity, p = 0.001 and 0.020, respectively), with modest and nonsignificant changes after anodal tDCS (p = 0.063 and 0.069, respectively). No significant differences in local rsFC were observed among the conditions. Correlations were observed between the E-field and rsFC changes in the L-DLPFC (r = 0.385, p = 0.115), left inferior parietal area (r = 0.495, p = 0.037), and right lateral visual area (r = 0.683, p = 0.002). Single-session tDCS induced resting brain activity changes and may help maintain overall rsFC. The E-field in the L-DLPFC is associated with rsFC changes in both proximal and distally connected brain regions to the L-DLPFC.

Cortical Layer-Dependent Signaling in Cognition: Three Computational Modes of the Canonical Circuit.

The cerebral cortex performs computations via numerous six-layer modules. The operational dynamics of these modules were studied primarily in early sensory cortices using bottom-up computation for response selectivity as a model, which has been recently revolutionized by genetic approaches in mice. However, cognitive processes such as recall and imagery require top-down generative computation. The question of whether the layered module operates similarly in top-down generative processing as in bottom-up sensory processing has become testable by advances in the layer identification of recorded neurons in behaving monkeys. This review examines recent advances in laminar signaling in these two computations, using predictive coding computation as a common reference, and shows that each of these computations recruits distinct laminar circuits, particularly in layer 5, depending on the cognitive demands. These findings highlight many open questions, including how different interareal feedback pathways, originating from and terminating at different layers, convey distinct functional signals.

Interaction of the dorsolateral prefrontal cortex with the precuneal medial parietal cortex for the monitoring of information in working memory in the macaque monkey.

The executive control process of monitoring information in working memory depends on the mid-dorsolateral prefrontal cortical region (cytoarchitectonic areas 46 and 9/46) in interaction with the hippocampal memory system. Anatomical studies demonstrated strong connectivity between the mid-dorsolateral prefrontal cortex and the medial parietal area PGm that lies on the precuneus. Area PGm is also strongly connected with the attentional system on the lateral inferior parietal lobule (area PG) and the limbic retrosplenial/posterior cingulate region that interacts with the hippocampal memory system. Thus, in terms of anatomical connectivity, area PGm appears to be a critical node for the integration of executive control processing from the prefrontal cortex with the online attentional and memory related processing. This hypothesis was tested in macaque monkeys with the crossed unilateral lesion methodology. A unilateral lesion in the mid-dorsolateral prefrontal cortex was combined with a unilateral lesion in area PGm in the opposite hemisphere. The results demonstrated an impairment on the externally ordered working memory task that assesses the monitoring of information in working memory. Thus, the medial parietal area PGm is a critical node in mediating the functional interaction between the prefrontal region for the executive control process of monitoring information and the memory system.

High segregation and diminished global integration in large-scale brain functional networks enhances the perceptual binding of cross-modal stimuli.

Speech perception requires the binding of spatiotemporally disjoint auditory-visual cues. The corresponding brain network-level information processing can be characterized by two complementary mechanisms: functional segregation which refers to the localization of processing in either isolated or distributed modules across the brain, and integration which pertains to cooperation among relevant functional modules. Here, we demonstrate using functional magnetic resonance imaging recordings that subjective perceptual experience of multisensory speech stimuli, real and illusory, are represented in differential states of segregation-integration. We controlled the inter-subject variability of illusory/cross-modal perception parametrically, by introducing temporal lags in the incongruent auditory-visual articulations of speech sounds within the McGurk paradigm. The states of segregation-integration balance were captured using two alternative computational approaches. First, the module responsible for cross-modal binding of sensory signals defined as the perceptual binding network (PBN) was identified using standardized parametric statistical approaches and their temporal correlations with all other brain areas were computed. With increasing illusory perception, the majority of the nodes of PBN showed decreased cooperation with the rest of the brain, reflecting states of high segregation but reduced global integration. Second, using graph theoretic measures, the altered patterns of segregation-integration were cross-validated.

Bidirectional fear modulation by discrete anterior insular circuits in male mice.

The brain's ability to appraise threats and execute appropriate defensive responses is essential for survival in a dynamic environment. Humans studies have implicated the anterior insular cortex (aIC) in subjective fear regulation and its abnormal activity in fear/anxiety disorders. However, the complex aIC connectivity patterns involved in regulating fear remain under investigated. To address this, we recorded single units in the aIC of freely moving male mice that had previously undergone auditory fear conditioning, assessed the effect of optogenetically activating specific aIC output structures in fear, and examined the organization of aIC neurons projecting to the specific structures with retrograde tracing. Single-unit recordings revealed that a balanced number of aIC pyramidal neurons' activity either positively or negatively correlated with a conditioned tone-induced freezing (fear) response. Optogenetic manipulations of aIC pyramidal neuronal activity during conditioned tone presentation altered the expression of conditioned freezing. Neural tracing showed that non-overlapping populations of aIC neurons project to the amygdala or the medial thalamus, and the pathway bidirectionally modulated conditioned fear. Specifically, optogenetic stimulation of the aIC-amygdala pathway increased conditioned freezing, while optogenetic stimulation of the aIC-medial thalamus pathway decreased it. Our findings suggest that the balance of freezing-excited and freezing-inhibited neuronal activity in the aIC and the distinct efferent circuits interact collectively to modulate fear behavior.

Serotonin transporter knockout in rats reduces beta- and gamma-band functional connectivity between the orbitofrontal cortex and amygdala during auditory discrimination.

The orbitofrontal cortex and amygdala collaborate in outcome-guided decision-making through reciprocal projections. While serotonin transporter knockout (SERT-/-) rodents show changes in outcome-guided decision-making, and in orbitofrontal cortex and amygdala neuronal activity, it remains unclear whether SERT genotype modulates orbitofrontal cortex-amygdala synchronization. We trained SERT-/- and SERT+/+ male rats to execute a task requiring to discriminate between two auditory stimuli, one predictive of a reward (CS+) and the other not (CS-), by responding through nose pokes in opposite-side ports. Overall, task acquisition was not influenced by genotype. Next, we simultaneously recorded local field potentials in the orbitofrontal cortex and amygdala of both hemispheres while the rats performed the task. Behaviorally, SERT-/- rats showed a nonsignificant trend for more accurate responses to the CS-. Electrophysiologically, orbitofrontal cortex-amygdala synchronization in the beta and gamma frequency bands during response selection was significantly reduced and associated with decreased hubness and clustering coefficient in both regions in SERT-/- rats compared to SERT+/+ rats. Conversely, theta synchronization at the time of behavioral response in the port associated with reward was similar in both genotypes. Together, our findings reveal the modulation by SERT genotype of the orbitofrontal cortex-amygdala functional connectivity during an auditory discrimination task.

Nogo-A-mediated constraints on activity-dependent synaptic plasticity and associativity in rat hippocampal CA2 synapses.

Hippocampal area CA2 has garnered attention in recent times owing to its significant involvement in social memory and distinctive plasticity characteristics. Research has revealed that the CA2 region demonstrates a remarkable resistance to plasticity, particularly in the Schaffer Collateral (SC)-CA2 pathway. In this study we investigated the role of Nogo-A, a well-known axon growth inhibitor and more recently discovered plasticity regulator, in modulating plasticity within the CA2 region. The findings demonstrate that blocking Nogo-A in male rat hippocampal slices facilitates the establishment of both short-term and long-term plasticity in the SC-CA2 pathway, while having no impact on the Entorhinal Cortical (EC)-CA2 pathway. Additionally, the study reveals that inhibiting Nogo-A enables association between the SC and EC pathways. Mechanistically, we confirm that Nogo-A operates through its well-known co-receptor, p75 neurotrophin receptor (p75NTR), and its downstream signaling factor such as Rho-associated protein kinase (ROCK), as their inhibition also allows plasticity induction in the SC-CA2 pathway. Additionally, the induction of long-term depression (LTD) in both the EC and SC-CA2 pathways led to persistent LTD, which was not affected by Nogo-A inhibition. Our study demonstrates the involvement of Nogo-A mediated signaling mechanisms in limiting synaptic plasticity within the CA2 region.

Medial to lateral frontal functional connectivity mapping reveals the organization of cingulate cortex.

The functional organization of the frontal lobe is a source of debate, focusing on broad functional subdivisions, large-scale networks, or local refined specificities. Multiple neurocognitive models have tried to explain how functional interactions between cingulate and lateral frontal regions contribute to decision making and cognitive control, but their neuroanatomical bases remain unclear. We provide a detailed description of the functional connectivity between cingulate and lateral frontal regions using resting-state functional MRI in rhesus macaques. The analysis focuses on the functional connectivity of the rostral part of the cingulate sulcus with the lateral frontal cortex. Data-driven and seed-based analysis revealed three clusters within the cingulate sulcus organized along the rostro-caudal axis: the anterior, mid, and posterior clusters display increased functional connectivity with, respectively, the anterior lateral prefrontal regions, face-eye lateral frontal motor cortical areas, and hand lateral frontal motor cortex. The location of these clusters can be predicted in individual subjects based on morphological landmarks. These results suggest that the anterior cluster corresponds to the anterior cingulate cortex, whereas the posterior clusters correspond to the face-eye and hand cingulate motor areas within the anterior midcingulate cortex. These data provide a comprehensive framework to identify cingulate subregions based on functional connectivity and local organization.

Sex differences in large-scale brain network connectivity for mental rotation performance.

Mental rotation has emerged as an important predictor for success in science, technology, engineering, and math fields. Previous studies have shown that males and females perform mental rotation tasks differently. However, how the brain functions to support this difference remains poorly understood. Recent advancements in neuroimaging techniques have enabled the identification of sex differences in large-scale brain network connectivity. Using a classic mental rotation task with functional magnetic resonance imaging, the present study investigated whether there are any sex differences in large-scale brain network connectivity for mental rotation performance. Our results revealed that, relative to females, males exhibited less cross-network interaction (i.e. lower inter-network connectivity and participation coefficient) of the visual network but more intra-network integration (i.e. higher intra-network connectivity and local efficiency) and cross-network interaction (i.e. higher inter-network connectivity and participation coefficient) of the salience network. Across all participants, mental rotation performance was negatively correlated with cross-network interaction (i.e. participation coefficient) of the visual network, was positively correlated with cross-network interaction (i.e. inter-network connectivity) of the salience network, and was positively correlated with intra-network integration (i.e. local efficiency) of the somato-motor network. Interestingly, the cross-network integration indexes of both the visual and salience networks significantly mediated sex difference in mental rotation performance. The present findings suggest that large-scale brain network connectivity may constitute an essential neural basis for sex difference in mental rotation, and highlight the importance of considering sex as a research variable in investigating the complex network underpinnings of spatial cognition.

Adolescent Thalamoprefrontal Inhibition Leads to Changes in Intrinsic Prefrontal Network Connectivity.

Adolescent inhibition of thalamocortical projections from postnatal days P20 to 50 leads to long-lasting deficits in prefrontal cortex function and cognition in the adult mouse. While this suggests a role of thalamic activity in prefrontal cortex maturation, it is unclear how inhibition of these projections affects prefrontal circuitry during adolescence. Here, we used chemogenetic tools to inhibit thalamoprefrontal projections in male/female mice from P20 to P35 and measured synaptic inputs to prefrontal pyramidal neurons by layer (either II/III or V/VI) and projection target (mediodorsal thalamus (MD), nucleus accumbens (NAc), or callosal prefrontal projections) 24 h later using slice physiology. We found a decrease in the frequency of excitatory and inhibitory currents in layer II/III NAc and layer V/VI MD-projecting neurons while layer V/VI NAc-projecting neurons showed an increase in the amplitude of excitatory and inhibitory currents. Regarding cortical projections, the frequency of inhibitory but not excitatory currents was enhanced in contralateral mPFC-projecting neurons. Notably, despite these complex changes in individual levels of excitation and inhibition, the overall balance between excitation and inhibition in each cell was only altered in the contralateral mPFC projections. This finding suggests homeostatic regulation occurs within subcortically but not intracortical callosal-projecting neurons. Increased inhibition of intraprefrontal connectivity may therefore be particularly important for prefrontal cortex circuit maturation. Finally, we observed cognitive deficits in the adult mouse using this narrowed window of thalamocortical inhibition.

Opioid circuit opens path to pain relief.

Manipulation of neural circuits targeted by morphine enables pain relief without opioids.

Multi-timescale neural dynamics for multisensory integration.

Carrying out any everyday task, be it driving in traffic, conversing with friends or playing basketball, requires rapid selection, integration and segregation of stimuli from different sensory modalities. At present, even the most advanced artificial intelligence-based systems are unable to replicate the multisensory processes that the human brain routinely performs, but how neural circuits in the brain carry out these processes is still not well understood. In this Perspective, we discuss recent findings that shed fresh light on the oscillatory neural mechanisms that mediate multisensory integration (MI), including power modulations, phase resetting, phase-amplitude coupling and dynamic functional connectivity. We then consider studies that also suggest multi-timescale dynamics in intrinsic ongoing neural activity and during stimulus-driven bottom-up and cognitive top-down neural network processing in the context of MI. We propose a new concept of MI that emphasizes the critical role of neural dynamics at multiple timescales within and across brain networks, enabling the simultaneous integration, segregation, hierarchical structuring and selection of information in different time windows. To highlight predictions from our multi-timescale concept of MI, real-world scenarios in which multi-timescale processes may coordinate MI in a flexible and adaptive manner are considered.

The nucleus of solitary tract (NTS) synchronizes sleep-wake-state-dependent cortical activity through the parabrachial nucleus (PB) in rat.

BACKGROUND: The medullary nucleus of solitary tract (NTS) and its afferents of vagus nerve have long been investigated in regulation of cortical activity and sleep promotion. However, the underlying neural circuit by which the NTS regulates electroencephalogram (EEG) and sleep remain unclear. As the NTS has a strong projection to the pontine arousal site, the parabrachial nucleus (PB), we proposed the NTS via the pontine parabrachial nucleus (PB) regulates cortical activity and sleep. METHODS: We bilaterally and directly stimulated the NTS neurons by chemogenetic approach and NTS terminals in the PB by optogenetic approach and examined changes in EEG and sleep in rats. RESULTS: Opto- and chemo-stimulation of the NTS and NTS-PB pathway altered neither sleep amounts nor patterns; however, both stimulations consistently increased EEG delta (0.5-4.0 Hz) EEG power during non-rapid-eye-movement (NREM) sleep and alpha-beta (10-30 Hz) EEG power during wake and REM sleep. CONCLUSION: Our results indicate that the NTS via its projections to the PB synchronizes low frequency EEG during NREM sleep and high frequency EEG during wake and REM sleep. This pathway may serve the neural foundation for the vagus nerve stimulation (VNS) treating cortical disorders.

Convergent direct and indirect cortical streams shape avoidance decisions in mice via the midline thalamus.

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.

The Projection-Specific Noradrenergic Modulation of Perseverative Spatial Behavior in Adult Male Rats.

Adaptive behavior relies on efficient cognitive control. The anterior cingulate cortex (ACC) is a key node within the executive prefrontal network. The reciprocal connectivity between the locus ceruleus (LC) and ACC is thought to support behavioral reorganization triggered by the detection of an unexpected change. We transduced LC neurons with either excitatory or inhibitory chemogenetic receptors in adult male rats and trained rats on a spatial task. Subsequently, we altered LC activity and confronted rats with an unexpected change of reward locations. In a new spatial context, rats with decreased noradrenaline (NA) in the ACC entered unbaited maze arms more persistently which was indicative of perseveration. In contrast, the suppression of the global NA transmission reduced perseveration. Neither chemogenetic manipulation nor inactivation of the ACC by muscimol affected the rate of learning, possibly due to partial virus transduction of the LC neurons and/or the compensatory engagement of other prefrontal regions. Importantly, we observed behavioral deficits in rats with LC damage caused by virus injection. The latter finding highlights the importance of careful histological assessment of virus-transduced brain tissue as inadvertent damage of the targeted cell population due to virus neurotoxicity or other factors might cause unwanted side effects. Although the specific role of ACC in the flexibility of spatial behavior has not been convincingly demonstrated, our results support the beneficial role of noradrenergic transmission for an optimal function of the ACC. Overall, our findings suggest the LC exerts the projection-specific modulation of neural circuits mediating the flexibility of spatial behavior.

Transthalamic Pathways for Cortical Function.

The cerebral cortex contains multiple, distinct areas that individually perform specific computations. A particular strength of the cortex is the communication of signals between cortical areas that allows the outputs of these compartmentalized computations to influence and build on each other, thereby dramatically increasing the processing power of the cortex and its role in sensation, action, and cognition. Determining how the cortex communicates signals between individual areas is, therefore, critical for understanding cortical function. Historically, corticocortical communication was thought to occur exclusively by direct anatomical connections between areas that often sequentially linked cortical areas in a hierarchical fashion. More recently, anatomical, physiological, and behavioral evidence is accumulating indicating a role for the higher-order thalamus in corticocortical communication. Specifically, the transthalamic pathway involves projections from one area of the cortex to neurons in the higher-order thalamus that, in turn, project to another area of the cortex. Here, we consider the evidence for and implications of having two routes for corticocortical communication with an emphasis on unique processing available in the transthalamic pathway and the consequences of disorders and diseases that affect transthalamic communication.