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Neuron Nov 2023Safety assessment and threat evaluation are crucial for animals to live and survive in the wilderness. However, neural circuits underlying safety assessment and their...
Safety assessment and threat evaluation are crucial for animals to live and survive in the wilderness. However, neural circuits underlying safety assessment and their transformation to mediate flexibility of fear-induced defensive behaviors remain largely unknown. Here, we report that distinct neuronal populations in mouse anterior cingulate cortex (ACC) encode safety status by selectively responding under different contexts of auditory threats, with one preferably activated when an animal staysing in a self-deemed safe zone and another specifically activated in more dangerous environmental settings that led to escape behavior. The safety-responding neurons preferentially target the zona incerta (ZI), which suppresses the superior colliculus (SC) via its GABAergic projection, while the danger-responding neurons preferentially target and excite SC. These distinct corticofugal pathways antagonistically modulate SC responses to threat, resulting in context-dependent expression of fear reactions. Thus, ACC serves as a critical node to encode safety/danger assessment and mediate behavioral flexibility through differential top-down circuits.
Topics: Mice; Animals; Gyrus Cinguli; Fear; Superior Colliculi; Zona Incerta
PubMed: 37652003
DOI: 10.1016/j.neuron.2023.08.008 -
Nature Neuroscience Sep 2023Idiopathic autism spectrum disorder (ASD) is highly heterogeneous, and it remains unclear how convergent biological processes in affected individuals may give rise to...
Idiopathic autism spectrum disorder (ASD) is highly heterogeneous, and it remains unclear how convergent biological processes in affected individuals may give rise to symptoms. Here, using cortical organoids and single-cell transcriptomics, we modeled alterations in the forebrain development between boys with idiopathic ASD and their unaffected fathers in 13 families. Transcriptomic changes suggest that ASD pathogenesis in macrocephalic and normocephalic probands involves an opposite disruption of the balance between excitatory neurons of the dorsal cortical plate and other lineages such as early-generated neurons from the putative preplate. The imbalance stemmed from divergent expression of transcription factors driving cell fate during early cortical development. While we did not find genomic variants in probands that explained the observed transcriptomic alterations, a significant overlap between altered transcripts and reported ASD risk genes affected by rare variants suggests a degree of gene convergence between rare forms of ASD and the developmental transcriptome in idiopathic ASD.
Topics: Male; Humans; Autistic Disorder; Autism Spectrum Disorder; Neurons; Neurogenesis; Prosencephalon; Organoids
PubMed: 37563294
DOI: 10.1038/s41593-023-01399-0 -
Nature Communications Oct 2023The ventral striatum is a reward center implicated in the pathophysiology of depression. It contains islands of Calleja, clusters of dopamine D3 receptor-expressing...
The ventral striatum is a reward center implicated in the pathophysiology of depression. It contains islands of Calleja, clusters of dopamine D3 receptor-expressing granule cells, predominantly in the olfactory tubercle (OT). These OT D3 neurons regulate self-grooming, a repetitive behavior manifested in affective disorders. Here we show that chronic restraint stress (CRS) induces robust depression-like behaviors in mice and decreases excitability of OT D3 neurons. Ablation or inhibition of these neurons leads to depression-like behaviors, whereas their activation ameliorates CRS-induced depression-like behaviors. Moreover, activation of OT D3 neurons has a rewarding effect, which diminishes when grooming is blocked. Finally, we propose a model that explains how OT D3 neurons may influence dopamine release via synaptic connections with OT spiny projection neurons (SPNs) that project to midbrain dopamine neurons. Our study reveals a crucial role of OT D3 neurons in bidirectionally mediating depression-like behaviors, suggesting a potential therapeutic target.
Topics: Mice; Animals; Islands of Calleja; Depression; Ventral Striatum; Olfactory Tubercle; Dopaminergic Neurons
PubMed: 37898623
DOI: 10.1038/s41467-023-42662-z -
Nature Apr 2024Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions. TS type 1 (TS1) is...
Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions. TS type 1 (TS1) is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched CACNA1C exon 8A, as opposed to its counterpart exon 8. We previously uncovered several phenotypes in neurons derived from patients with TS1, including delayed channel inactivation, prolonged depolarization-induced calcium rise, impaired interneuron migration, activity-dependent dendrite retraction and an unanticipated persistent expression of exon 8A. We reasoned that switching CACNA1C exon utilization from 8A to 8 would represent a potential therapeutic strategy. Here we developed antisense oligonucleotides (ASOs) to effectively decrease the inclusion of exon 8A in human cells both in vitro and, following transplantation, in vivo. We discovered that the ASO-mediated switch from exon 8A to 8 robustly rescued defects in patient-derived cortical organoids and migration in forebrain assembloids. Leveraging a transplantation platform previously developed, we found that a single intrathecal ASO administration rescued calcium changes and in vivo dendrite retraction of patient neurons, suggesting that suppression of CACNA1C exon 8A expression is a potential treatment for TS1. Broadly, these experiments illustrate how a multilevel, in vivo and in vitro stem cell model-based approach can identify strategies to reverse disease-relevant neural pathophysiology.
Topics: Animals; Female; Humans; Male; Mice; Alternative Splicing; Autistic Disorder; Calcium; Calcium Channels, L-Type; Cell Movement; Dendrites; Exons; Long QT Syndrome; Neurons; Oligonucleotides, Antisense; Organoids; Prosencephalon; Syndactyly; Interneurons
PubMed: 38658687
DOI: 10.1038/s41586-024-07310-6 -
Cellular & Molecular Immunology Nov 2023To define the systemic neuroimmune interactions in health and disease, we recently suggested immunoception as a term that refers to the existence of bidirectional... (Review)
Review
To define the systemic neuroimmune interactions in health and disease, we recently suggested immunoception as a term that refers to the existence of bidirectional functional loops between the brain and the immune system. This concept suggests that the brain constantly monitors changes in immune activity and, in turn, can regulate the immune system to generate a physiologically synchronized response. Therefore, the brain has to represent information regarding the state of the immune system, which can occure in multiple ways. One such representation is an immunengram, a trace that is partially stored by neurons and partially by the local tissue. This review will discuss our current understanding of immunoception and immunengrams, focusing on their manifestation in a specific brain region, the insular cortex (IC).
Topics: Insular Cortex; Cerebral Cortex; Neurons
PubMed: 37386172
DOI: 10.1038/s41423-023-01051-8 -
Cell Reports Jul 2023The neural circuit mechanisms underlying postoperative cognitive dysfunction (POCD) remain elusive. We hypothesized that projections from the medial prefrontal cortex...
The neural circuit mechanisms underlying postoperative cognitive dysfunction (POCD) remain elusive. We hypothesized that projections from the medial prefrontal cortex (mPFC) to the amygdala are involved in POCD. A mouse model of POCD in which isoflurane (1.5%) combined with laparotomy was used. Virally assisted tracing techniques were used to label the relevant pathways. Fear conditioning, immunofluorescence, whole-cell patch-clamp recordings, and chemogenetic and optogenetic techniques were applied to investigate the role of mPFC-amygdala projections in POCD. We find that surgery impairs memory consolidation but not retrieval of consolidated memories. In POCD mice, the glutamatergic pathway from the prelimbic cortex to the basolateral amygdala (PL-BLA) shows reduced activity, whereas the glutamatergic pathway from the infralimbic cortex to the basomedial amygdala (IL-BMA) shows enhanced activity. Our study indicates that the hypoactivity in the PL-BLA pathway interrupts memory consolidation, whereas the hyperactivity in the IL-BMA promotes memory extinction, in POCD mice.
Topics: Mice; Animals; Prefrontal Cortex; Amygdala; Basolateral Nuclear Complex; Cerebral Cortex; Memory Disorders; Neural Pathways
PubMed: 37392387
DOI: 10.1016/j.celrep.2023.112719 -
Cold Spring Harbor Perspectives in... Jan 2024Conscious perception in mammals depends on precise circuit connectivity between cerebral cortex and thalamus; the evolution and development of these structures are... (Review)
Review
Conscious perception in mammals depends on precise circuit connectivity between cerebral cortex and thalamus; the evolution and development of these structures are closely linked. During the wiring of reciprocal thalamus-cortex connections, thalamocortical axons (TCAs) first navigate forebrain regions that had undergone substantial evolutionary modifications. In particular, the organization of the pallial-subpallial boundary (PSPB) diverged significantly between mammals, reptiles, and birds. In mammals, transient cell populations in internal capsule and early corticofugal projections from subplate neurons closely interact with TCAs to guide pathfinding through ventral forebrain and PSPB crossing. Prior to thalamocortical axon arrival, cortical areas are initially patterned by intrinsic genetic factors. Thalamocortical axons then innervate cortex in a topographically organized manner to enable sensory input to refine cortical arealization. Here, we review the mechanisms underlying the guidance of thalamocortical axons across forebrain boundaries, the implications of PSPB evolution for thalamocortical axon pathfinding, and the reciprocal influence between thalamus and cortex during development.
Topics: Animals; Thalamus; Neurons; Axons; Cerebral Cortex; Mammals; Neural Pathways
PubMed: 38167425
DOI: 10.1101/cshperspect.a041503 -
The Journal of Neuroscience : the... Nov 2023The supramammillary nucleus (SuM) is a small region in the ventromedial posterior hypothalamus. The SuM has been relatively understudied with much of the prior focus... (Review)
Review
The supramammillary nucleus (SuM) is a small region in the ventromedial posterior hypothalamus. The SuM has been relatively understudied with much of the prior focus being on its connection with septo-hippocampal circuitry. Thus, most studies conducted until the 21st century examined its role in hippocampal processes, such as theta rhythm and learning/memory. In recent years, the SuM has been "rediscovered" as a crucial hub for several behavioral and cognitive processes, including reward-seeking, exploration, and social memory. Additionally, it has been shown to play significant roles in hippocampal plasticity and adult neurogenesis. This review highlights findings from recent studies using cutting-edge systems neuroscience tools that have shed light on these fascinating roles for the SuM.
Topics: Motivation; Hypothalamus, Posterior; Hippocampus; Theta Rhythm; Cognition
PubMed: 37940587
DOI: 10.1523/JNEUROSCI.1320-23.2023 -
Trends in Cognitive Sciences Mar 2024Many cognitive neuroscientists believe that both a large brain and an isocortex are crucial for complex cognition. Yet corvids and parrots possess non-cortical brains of... (Review)
Review
Many cognitive neuroscientists believe that both a large brain and an isocortex are crucial for complex cognition. Yet corvids and parrots possess non-cortical brains of just 1-25 g, and these birds exhibit cognitive abilities comparable with those of great apes such as chimpanzees, which have brains of about 400 g. This opinion explores how this cognitive equivalence is possible. We propose four features that may be required for complex cognition: a large number of associative pallial neurons, a prefrontal cortex (PFC)-like area, a dense dopaminergic innervation of association areas, and dynamic neurophysiological fundaments for working memory. These four neural features have convergently evolved and may therefore represent 'hard to replace' mechanisms enabling complex cognition.
Topics: Animals; Birds; Cognition; Neocortex; Prefrontal Cortex
PubMed: 38097447
DOI: 10.1016/j.tics.2023.11.002 -
Neuron Mar 2024Executive control, the ability to organize thoughts and action plans in real time, is a defining feature of higher cognition. Classical theories have emphasized cortical... (Review)
Review
Executive control, the ability to organize thoughts and action plans in real time, is a defining feature of higher cognition. Classical theories have emphasized cortical contributions to this process, but recent studies have reinvigorated interest in the role of the thalamus. Although it is well established that local thalamic damage diminishes cognitive capacity, such observations have been difficult to inform functional models. Recent progress in experimental techniques is beginning to enrich our understanding of the anatomical, physiological, and computational substrates underlying thalamic engagement in executive control. In this review, we discuss this progress and particularly focus on the mediodorsal thalamus, which regulates the activity within and across frontal cortical areas. We end with a synthesis that highlights frontal thalamocortical interactions in cognitive computations and discusses its functional implications in normal and pathological conditions.
Topics: Executive Function; Neural Pathways; Thalamus; Cognition; Frontal Lobe; Prefrontal Cortex
PubMed: 38295791
DOI: 10.1016/j.neuron.2024.01.002