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Social behaviors are crucial to all mammals. Although the prelimbic cortex (PL, part of medial prefrontal cortex) has been implicated in social behavior, it is not clear which neurons are relevant or how they contribute. We found that PL contains anatomically and molecularly distinct subpopulations that target three downstream regions that have been implicated in social behavior: the nucleus accumbens (NAc), amygdala, and ventral tegmental area. Activation of NAc-projecting PL neurons (PL-NAc), but not the other subpopulations, decreased the preference for a social target. To determine what information PL-NAc neurons convey, we selectively recorded from them and found that individual neurons were active during social investigation, but only in specific spatial locations. Spatially specific manipulation of these neurons bidirectionally regulated the formation of a social-spatial association. Thus, the unexpected combination of social and spatial information within the PL-NAc may contribute to social behavior by supporting social-spatial learning.
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Sistema Límbico , Neuronas/citología , Núcleo Accumbens/citología , Corteza Prefrontal/citología , Conducta Social , Conducta Espacial , Amígdala del Cerebelo/fisiología , Animales , Aprendizaje , Ratones , Vías Nerviosas , Neuronas/fisiología , Núcleo Accumbens/fisiología , Corteza Prefrontal/fisiología , Área Tegmental Ventral/fisiologíaRESUMEN
Reward-seeking behavior is fundamental to survival, but suppression of this behavior can be essential as well, even for rewards of high value. In humans and rodents, the medial prefrontal cortex (mPFC) has been implicated in suppressing reward seeking; however, despite vital significance in health and disease, the neural circuitry through which mPFC regulates reward seeking remains incompletely understood. Here, we show that a specific subset of superficial mPFC projections to a subfield of nucleus accumbens (NAc) neurons naturally encodes the decision to initiate or suppress reward seeking when faced with risk of punishment. A highly resolved subpopulation of these top-down projecting neurons, identified by 2-photon Ca2+ imaging and activity-dependent labeling to recruit the relevant neurons, was found capable of suppressing reward seeking. This natural activity-resolved mPFC-to-NAc projection displayed unique molecular-genetic and microcircuit-level features concordant with a conserved role in the regulation of reward-seeking behavior, providing cellular and anatomical identifiers of behavioral and possible therapeutic significance.
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Recompensa , Animales , Conducta Animal , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Vías Nerviosas , Neuroimagen , Corteza Prefrontal/citología , Corteza Prefrontal/metabolismo , CastigoRESUMEN
As a frontal node in the primate social brain, the medial prefrontal cortex (MPFC) plays a critical role in coordinating one's own behavior with respect to that of others. Current literature demonstrates that single neurons in the MPFC encode behavior-related variables such as intentions, actions, and rewards, specifically for self and other, and that the MPFC comes into play when reflecting upon oneself and others. The social moderator account of MPFC function can explain maladaptive social cognition in people with autism spectrum disorder, which tips the balance in favor of self-centered perspectives rather than taking into consideration the perspective of others. Several strands of evidence suggest a hypothesis that the MPFC represents different other mental models, depending on the context at hand, to better predict others' emotions and behaviors. This hypothesis also accounts for aberrant MPFC activity in autistic individuals while they are mentalizing others.
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Trastorno del Espectro Autista , Imagen por Resonancia Magnética , Animales , Mapeo Encefálico , Corteza Prefrontal , PrimatesRESUMEN
Modulation of neuronal firing rates by the spatial locations of physical objects is a widespread phenomenon in the brain. However, little is known about how neuronal responses to the actions of biological entities are spatially tuned and whether such spatially tuned responses are affected by social contexts. These issues are of key importance for understanding the neural basis of embodied social cognition, such as imitation and perspective-taking. Here, we show that spatial representation of actions can be dynamically changed depending on others' social relevance and agents of action. Monkeys performed a turn-taking choice task with a real monkey partner sitting face-to-face or a filmed partner in prerecorded videos. Three rectangular buttons (left, center, and right) were positioned in front of the subject and partner as their choice targets. We recorded from single neurons in two frontal nodes in the social brain, the ventral premotor cortex (PMv) and the medial prefrontal cortex (MPFC). When the partner was filmed rather than real, spatial preference for partner-actions was markedly diminished in MPFC, but not PMv, neurons. This social context-dependent modulation in the MPFC was also evident for self-actions. Strikingly, a subset of neurons in both areas switched their spatial preference between self-actions and partner-actions in a diametrically opposite manner. This observation suggests that these cortical areas are associated with coordinate transformation in ways consistent with an actor-centered perspective-taking coding scheme. The PMv may subserve such functions in context-independent manners, whereas the MPFC may do so primarily in social contexts.
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Lóbulo Frontal , Animales , Masculino , Lóbulo Frontal/fisiología , Macaca mulatta , Neuronas/fisiología , Corteza Prefrontal/fisiología , Percepción Espacial/fisiología , MacacaRESUMEN
The medial prefrontal cortex (mPFC) is a key brain structure for higher cognitive functions such as decision-making and goal-directed behavior, many of which require awareness of spatial variables including one's current position within the surrounding environment. Although previous studies have reported spatially tuned activities in mPFC during memory-related trajectory, the spatial tuning of mPFC network during freely foraging behavior remains elusive. Here, we reveal geometric border or border-proximal representations from the neural activity of mPFC ensembles during naturally exploring behavior, with both allocentric and egocentric boundary responses. Unlike most of classical border cells in the medial entorhinal cortex (MEC) discharging along a single wall, a large majority of border cells in mPFC fire particularly along four walls. mPFC border cells generate new firing fields to external insert, and remain stable under darkness, across distinct shapes, and in novel environments. In contrast to hippocampal theta entrainment during spatial working memory tasks, mPFC border cells rarely exhibited theta rhythmicity during spontaneous locomotion behavior. These findings reveal spatially modulated activity in mPFC, supporting local computation for cognitive functions involving spatial context and contributing to a broad spatial tuning property of cortical circuits.
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Corteza Prefrontal , Ritmo Teta , Corteza Prefrontal/fisiología , Corteza Prefrontal/citología , Animales , Ritmo Teta/fisiología , Masculino , Ratones , Corteza Entorrinal/fisiología , Neuronas/fisiología , Hipocampo/fisiología , Memoria Espacial/fisiología , Ratones Endogámicos C57BL , Memoria a Corto Plazo/fisiologíaRESUMEN
Schizophrenia is a serious mental disorder, and existing antipsychotic drugs show limited efficacy and cause unwanted side effects. The development of glutamatergic drugs for schizophrenia is currently challenging. Most functions of histamine in the brain are mediated by the histamine H1 receptor; however, the role of the H2 receptor (H2R) is not quite clear, especially in schizophrenia. Here, we found that expression of H2R in glutamatergic neurons of the frontal cortex was decreased in schizophrenia patients. Selective knockout of the H2R gene (Hrh2) in glutamatergic neurons (CaMKIIα-Cre; Hrh2 fl/fl) induced schizophrenia-like phenotypes including sensorimotor gating deficits, increased susceptibility to hyperactivity, social withdrawal, anhedonia, and impaired working memory, as well as decreased firing of glutamatergic neurons in the medial prefrontal cortex (mPFC) in in vivo electrophysiological tests. Selective knockdown of H2R in glutamatergic neurons in the mPFC but not those in the hippocampus also mimicked these schizophrenia-like phenotypes. Furthermore, electrophysiology experiments established that H2R deficiency decreased the firing of glutamatergic neurons by enhancing the current through hyperpolarization-activated cyclic nucleotide-gated channels. In addition, either H2R overexpression in glutamatergic neurons or H2R agonism in the mPFC counteracted schizophrenia-like phenotypes in an MK-801-induced mouse model of schizophrenia. Taken together, our results suggest that deficit of H2R in mPFC glutamatergic neurons may be pivotal to the pathogenesis of schizophrenia and that H2R agonists can be regarded as potentially efficacious medications for schizophrenia therapy. The findings also provide evidence for enriching the conventional glutamate hypothesis for the pathogenesis of schizophrenia and improve the understanding of the functional role of H2R in the brain, especially in glutamatergic neurons.
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Histamina , Esquizofrenia , Ratones , Animales , Histamina/metabolismo , Neuronas/metabolismo , Receptores Histamínicos H2 , Memoria a Corto PlazoRESUMEN
Acetylcholine is a robust neuromodulator of the limbic system and a critical regulator of arousal and emotions. The anterior cingulate cortex (ACC) and the amygdala (AMY) are key limbic structures that are both densely innervated by cholinergic afferents and interact with each other for emotional regulation. The ACC is composed of functionally distinct dorsal (A24), rostral (A32), and ventral (A25) areas that differ in their connections with the AMY. The structural substrates of cholinergic modulation of distinct ACC microcircuits and outputs to AMY are thought to depend on the laminar and subcellular localization of cholinergic receptors. The present study examines the distribution of muscarinic acetylcholine receptors, m1 and m2, on distinct excitatory and inhibitory neurons and on AMY-targeting projection neurons within ACC areas, via immunohistochemistry and injections of neural tracers into the basolateral AMY in adult rhesus monkeys of both sexes. We found that laminar densities of m1+ and m2+ expressing excitatory and inhibitory neurons depended on area and cell type. Among the ACC areas, ventral subgenual ACC A25 exhibited greater m2+ localization on presynaptic inhibitory axon terminals and greater density of m1+ and m2+ expressing AMY-targeting (tracer+) pyramidal neurons. These patterns suggest robust cholinergic disinhibition and potentiation of amygdalar outputs from the limbic ventral ACC, which may be linked to the hyperexcitability of this subgenual ACC area in depression. These findings reveal the anatomical substrate of diverse cholinergic modulation of specific ACC microcircuits and amygdalar outputs that mediate cognitive-emotional integration and dysfunctions underlying stress and affective disorders.
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Giro del Cíngulo , Macaca mulatta , Animales , Giro del Cíngulo/metabolismo , Giro del Cíngulo/fisiología , Masculino , Femenino , Receptor Muscarínico M2/metabolismo , Receptor Muscarínico M1/metabolismo , Red Nerviosa/metabolismo , Red Nerviosa/fisiología , Acetilcolina/metabolismo , Vías Nerviosas/fisiología , Vías Nerviosas/metabolismo , Neuronas/metabolismo , Neuronas/fisiologíaRESUMEN
Creative idea generation plays an important role in promoting successful memory formation. Yet, its underlying neural correlates remain unclear. We investigated the self-generated learning of creative ideas motivated by the schema-linked interactions between medial prefrontal and medial temporal regions framework. This was achieved by having participants generate ideas in the alternative uses task, self-evaluating their ideas based on novelty and source (i.e. new or old), and then later being tested on the recognition performance of the generated ideas. At the behavioral level, our results indicated superior performances in discriminating novel ideas, highlighting the novelty effect on memory. At the neural level, the regions-of-interest analyses revealed that successful recognition of novel ideas was associated with greater activations in the hippocampus (HPC) and medial prefrontal cortex (mPFC) during ideation. However, only activation in the right HPC was positively related to the successful recognition of novel ideas. Importantly, the weaker the connection between the right HPC and left mPFC, the higher the recognition accuracy of novel ideas. Moreover, activations in the right HPC and left mPFC were both effective predictors of successful recognition of novel ideas. These findings uniquely highlight the role of novelty in promoting self-generated learning of creative ideas.
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Creatividad , Hipocampo , Aprendizaje , Imagen por Resonancia Magnética , Corteza Prefrontal , Reconocimiento en Psicología , Corteza Prefrontal/fisiología , Humanos , Masculino , Hipocampo/fisiología , Femenino , Adulto Joven , Aprendizaje/fisiología , Adulto , Reconocimiento en Psicología/fisiología , Mapeo Encefálico/métodosRESUMEN
Spontaneous and conversational laughter are important socio-emotional communicative signals. Neuroimaging findings suggest that non-autistic people engage in mentalizing to understand the meaning behind conversational laughter. Autistic people may thus face specific challenges in processing conversational laughter, due to their mentalizing difficulties. Using fMRI, we explored neural differences during implicit processing of these two types of laughter. Autistic and non-autistic adults passively listened to funny words, followed by spontaneous laughter, conversational laughter, or noise-vocoded vocalizations. Behaviourally, words plus spontaneous laughter were rated as funnier than words plus conversational laughter, and the groups did not differ. However, neuroimaging results showed that non-autistic adults exhibited greater medial prefrontal cortex activation while listening to words plus conversational laughter, than words plus genuine laughter, while autistic adults showed no difference in medial prefrontal cortex activity between these two laughter types. Our findings suggest a crucial role for the medial prefrontal cortex in understanding socio-emotionally ambiguous laughter via mentalizing. Our study also highlights the possibility that autistic people may face challenges in understanding the essence of the laughter we frequently encounter in everyday life, especially in processing conversational laughter that carries complex meaning and social ambiguity, potentially leading to social vulnerability. Therefore, we advocate for clearer communication with autistic people.
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Trastorno Autístico , Mapeo Encefálico , Encéfalo , Risa , Imagen por Resonancia Magnética , Humanos , Risa/fisiología , Risa/psicología , Masculino , Femenino , Adulto , Trastorno Autístico/fisiopatología , Trastorno Autístico/diagnóstico por imagen , Trastorno Autístico/psicología , Adulto Joven , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Encéfalo/fisiología , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/fisiopatología , Corteza Prefrontal/fisiología , Estimulación AcústicaRESUMEN
Neuromodulatory substances can be released from distal afferents for communication between brain structures or produced locally to modulate neighboring circuit elements. Corticotropin-releasing hormone (CRH) from long-range neurons in the hypothalamus projecting to the medial prefrontal cortex (mPFC) has been shown to induce anxiety-like behaviors. However, the role of CRH produced in the mPFC has not been investigated. Here we demonstrate that a specific class of mPFC interneurons that express CRH (CrhINs) releases CRH upon high-frequency stimulation to enhance excitability of layer 2/3 pyramidal cells (L2/3 PCs) expressing the CRH receptors. When stimulated at low frequency, CrhINs release GABA resulting in the inhibition of oxytocin receptor-expressing interneurons (OxtrINs) and L2/3 PCs. Conditional deletion of CRH in mPFC CrhINs and chemogenetic activation of CrhINs have opposite effects on novelty exploration in male but not in female mice, and do not affect anxiety-related behaviors in either males or females. Our data reveal that CRH produced by local interneurons in the mPFC is required for sex-specific novelty exploration and suggest that our understanding of complex behaviors may require knowledge of local and remote neuromodulatory action.
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Hormona Liberadora de Corticotropina , Corteza Prefrontal , Femenino , Masculino , Animales , Ratones , Hormona Liberadora de Corticotropina/genética , Receptores de Hormona Liberadora de Corticotropina , Células Piramidales , InterneuronasRESUMEN
BACKGROUND: The medial prefrontal cortex (mPFC) is involved in complex functions containing multiple types of neurons in distinct subregions with preferential roles. The pyramidal neurons had wide-range projections to cortical and subcortical regions with subregional preferences. Using a combination of viral tracing and fluorescence micro-optical sectioning tomography (fMOST) in transgenic mice, we systematically dissected the whole-brain connectomes of intratelencephalic (IT) and pyramidal tract (PT) neurons in four mPFC subregions. RESULTS: IT and PT neurons of the same subregion projected to different target areas while receiving inputs from similar upstream regions with quantitative differences. IT and PT neurons all project to the amygdala and basal forebrain, but their axons target different subregions. Compared to subregions in the prelimbic area (PL) which have more connections with sensorimotor-related regions, the infralimbic area (ILA) has stronger connections with limbic regions. The connection pattern of the mPFC subregions along the anterior-posterior axis showed a corresponding topological pattern with the isocortex and amygdala but an opposite orientation correspondence with the thalamus. CONCLUSIONS: By using transgenic mice and fMOST imaging, we obtained the subregional preference whole-brain connectomes of IT and pyramidal tract PT neurons in the mPFC four subregions. These results provide a comprehensive resource for directing research into the complex functions of the mPFC by offering anatomical dissections of the different subregions.
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Conectoma , Ratones Transgénicos , Corteza Prefrontal , Células Piramidales , Animales , Corteza Prefrontal/fisiología , Corteza Prefrontal/citología , Células Piramidales/fisiología , Ratones , MasculinoRESUMEN
Itch is an uncomfortable and complex sensation that elicits the desire to scratch. The nucleus accumbens (NAc) activity is important in driving sensation, motivation, and emotion. Excitatory afferents from the medial prefrontal cortex (mPFC), amygdala, and hippocampus are crucial in tuning the activity of dopamine receptor D1-expressing and D2-expressing medium spiny neurons (Drd1-MSN and Drd2-MSN) in the NAc. However, a cell-type and neural circuity-based mechanism of the NAc underlying acute itch remains unclear. We found that acute itch induced by compound 48/80 (C48/80) decreased the intrinsic membrane excitability in Drd1-MSNs, but not in Drd2-MSNs, in the NAc core of male mice. Chemogenetic activation of Drd1-MSNs alleviated C48/80-induced scratching behaviors but not itch-related anxiety-like behaviors. In addition, C48/80 enhanced the frequency of spontaneous EPSCs (sEPSCs) and reduced the paired-pulse ratio (PPR) of electrical stimulation-evoked EPSCs in Drd1-MSNs. Furthermore, C48/80 increased excitatory synaptic afferents to Drd1-MSNs from the mPFC, not from the basolateral amygdala (BLA) or ventral hippocampus (vHipp). Consistently, the intrinsic excitability of mPFC-NAc projecting pyramidal neurons was increased after C48/80 treatment. Chemogenetic inhibition of mPFC-NAc excitatory synaptic afferents relieved the scratching behaviors. Moreover, pharmacological activation of κ opioid receptor (KOR) in the NAc core suppressed C48/80-induced scratching behaviors, and the modulation of KOR activity in the NAc resulted in the changes of presynaptic excitatory inputs to Drd1-MSNs in C48/80-treated mice. Together, these results reveal the neural plasticity in synapses of NAc Drd1-MSNs from the mPFC underlying acute itch and indicate the modulatory role of the KOR in itch-related scratching behaviors.SIGNIFICANCE STATEMENT Itch stimuli cause strongly scratching desire and anxiety in patients. However, the related neural mechanisms remain largely unclear. In the present study, we demonstrated that the pruritogen compound 48/80 (C48/80) shapes the excitability of dopamine receptor D1-expressing medium spiny neurons (Drd1-MSNs) in the nucleus accumbens (NAc) core and the glutamatergic synaptic afferents from medial prefrontal cortex (mPFC) to these neurons. Chemogenetic activation of Drd1-MSNs or inhibition of mPFC-NAc excitatory synaptic afferents relieves the scratching behaviors. In addition, pharmacological activation of κ opioid receptor (KOR) in the NAc core alleviates C48/80-induced itch. Thus, targeting mPFC-NAc Drd1-MSNs or KOR may provide effective treatments for itch.
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Núcleo Accumbens , Receptores Opioides kappa , Ratones , Masculino , Animales , Núcleo Accumbens/fisiología , Hipocampo/fisiología , Neuronas/fisiología , Receptores de Dopamina D1/metabolismo , Corteza Prefrontal/metabolismoRESUMEN
Synaptic changes play a major role in memory processes. Modulation of synaptic responses by brain states remains, however, poorly understood in hippocampal networks, even in basal conditions. We recorded evoked synaptic responses at five hippocampal pathways in freely moving male rats. We showed that, at the perforant path to dentate gyrus (PP-DG) synapse, responses increase during wakefulness compared with sleep. At the Schaffer collaterals to CA1 (SC-CA1) synapse, responses increase during non-REM sleep (NREM) compared with the other states. During REM sleep (REM), responses decreased at the PP-DG and SC-CA1 synapses compared with NREM, while they increased at the fornix to nucleus accumbens synapse (Fx-NAc) during REM compared with the other states. In contrast, responses at the fornix to medial PFC synapse (Fx-PFC) and at the fornix to amygdala synapse (Fx-Amy) were weakly modulated by vigilance states. Extended sleep periods led to synaptic changes at PP-DG and Fx-Amy synapses but not at the other synapses. Synaptic responses were also linked to local oscillations and were highly correlated between Fx-PFC and Fx-NAc but not between Fx-Amy and these synapses. These results reveal synapse-specific modulations that may contribute to memory consolidation during the sleep-wake cycle.SIGNIFICANCE STATEMENT Surprisingly, the cortical network dynamics remains poorly known at the synaptic level. We tested the hypothesis that brain states would modulate synaptic changes in the same way at different cortical connections. To tackle this issue, we implemented an approach to explore the synaptic behavior of five connections upstream and downstream the rat hippocampus. Our study reveals that synaptic responses are modulated in a highly synapse-specific manner by wakefulness and sleep states as well as by local oscillations at these connections. Moreover, we found rapid synaptic changes during wake and sleep transitions as well as synaptic down and upregulations after extended periods of sleep. These synaptic changes are likely related to the mechanisms of sleep-dependent memory consolidation.
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Hipocampo , Sinapsis , Ratas , Masculino , Animales , Hipocampo/fisiología , Sinapsis/fisiología , Sueño/fisiología , Encéfalo , Vía Perforante/fisiologíaRESUMEN
Olfactory dysfunction is often the earliest indicator of disease in a range of neurological and psychiatric disorders. One tempting working hypothesis is that pathological changes in the peripheral olfactory system where the body is exposed to many adverse environmental stressors may have a causal role for the brain alteration. Whether and how the peripheral pathology spreads to more central brain regions may be effectively studied in rodent models, and there is successful precedence in experimental models for Parkinson's disease. It is of interest to study whether a similar mechanism may underlie the pathology of psychiatric illnesses, such as schizophrenia. However, direct comparison between rodent models and humans includes challenges under light of comparative neuroanatomy and experimental methodologies used in these two distinct species. We believe that neuroimaging modality that has been the main methodology of human brain studies may be a useful viewpoint to address and fill the knowledge gap between rodents and humans in this scientific question. Accordingly, in the present review article, we focus on brain imaging studies associated with olfaction in healthy humans and patients with neurological and psychiatric disorders, and if available those in rodents. We organize this review article at three levels: 1) olfactory bulb (OB) and peripheral structures of the olfactory system, 2) primary olfactory cortical and subcortical regions, and 3) associated higher-order cortical regions. This research area is still underdeveloped, and we acknowledge that further validation with independent cohorts may be needed for many studies presented here, in particular those with human subjects. Nevertheless, whether and how peripheral olfactory disturbance impacts brain function is becoming even a hotter topic in the ongoing COVID-19 pandemic, given the risk of long-term changes of mental status associated with olfactory infection of SARS-CoV-2. Together, in this review article, we introduce this underdeveloped but important research area focusing on its implications in neurological and psychiatric disorders, with several pioneered publications.
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COVID-19 , Trastornos del Olfato , Humanos , Neuroimagen/efectos adversos , Trastornos del Olfato/diagnóstico por imagen , Trastornos del Olfato/etiología , Trastornos del Olfato/patología , Bulbo Olfatorio/anatomía & histología , Bulbo Olfatorio/patología , Pandemias , SARS-CoV-2 , OlfatoRESUMEN
Olfactory dysfunction is manifested in a wide range of neurological and psychiatric diseases, and often emerges prior to the onset of more classical symptoms and signs. From a behavioral perspective, olfactory deficits typically arise in conjunction with impairments of cognition, motivation, memory, and emotion. However, a conceptual framework for explaining the impact of olfactory processing on higher brain functions in health and disease remains lacking. Here we aim to provide circuit-level insights into this question by synthesizing recent advances in olfactory network connectivity with other cortical brain regions such as the prefrontal cortex. We will focus on social cognition as a representative model for exploring and critically evaluating the relationship between olfactory cortices and higher-order cortical regions in rodent models. Although rodents do not recapitulate all dimensions of human social cognition, they have experimentally accessible neural circuits and well-established behavioral tests for social motivation, memory/recognition, and hierarchy, which can be extrapolated to other species including humans. In particular, the medial prefrontal cortex (mPFC) has been recognized as a key brain region in mediating social cognition in both rodents and humans. This review will highlight the underappreciated connectivity, both anatomical and functional, between the olfactory system and mPFC circuitry, which together provide a neural substrate for olfactory modulation of social cognition and social behaviors. We will provide future perspectives on the functional investigation of the olfactory-mPFC circuit in rodent models and discuss how to translate such animal research to human studies.
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Corteza Prefrontal , Cognición Social , Animales , Encéfalo , Cognición , Humanos , Conducta SocialRESUMEN
The adult brain retains a high repopulation capacity of astrocytes after deletion, and both mature astrocytes in the neocortex and neural stem cells in neurogenic regions possess the potential to generate astrocytes. However, the origin and the repopulation dynamics of the repopulating astrocytes after deletion remain largely unclear. The number of astrocytes is reduced in the medial prefrontal cortex (mPFC) of patients with depression, and selective elimination of mPFC astrocytes is sufficient to induce depression-like behaviors in rodents. However, whether astrocyte repopulation capacity is impaired in depression is unknown. In this study, we used different transgenic mouse lines to genetically label different cell types and demonstrated that in the mPFC of normal adult mice of both sexes, mature astrocytes were a major source of the repopulating astrocytes after acute deletion induced by an astrocyte-specific toxin, L-alpha-aminoadipic acid (L-AAA), and astrocyte regeneration was accomplished within two weeks accompanied by reversal of depression-like behaviors. Furthermore, re-ablation of mPFC astrocytes post repopulation led to reappearance of depression-like behaviors. In adult male mice subjected to 14-day chronic restraint stress, a well-validated mouse model of depression, the number of mPFC astrocytes was reduced; however, the ability of mPFC astrocytes to repopulate after L-AAA-induced deletion was largely unaltered. Our study highlights a potentially beneficial role for repopulating astrocytes in depression and provides novel therapeutic insights into enhancing local mature astrocyte generation in depression.
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Astrocitos , Depresión , Ratones Transgénicos , Corteza Prefrontal , Animales , Astrocitos/metabolismo , Corteza Prefrontal/metabolismo , Masculino , Depresión/genética , Depresión/patología , Femenino , Ratones Endogámicos C57BL , Ratones , Modelos Animales de Enfermedad , Restricción Física , Ácido 2-Aminoadípico , Estrés Psicológico/patología , Estrés Psicológico/metabolismoRESUMEN
The temporal component of episodic memory has been recognized as a sensitive behavioral marker in early stage of Alzheimer's disease (AD) patients. However, parallel studies in AD animals are currently lacking, and the underlying neural circuit mechanisms remain poorly understood. Using a novel AppNL-G-F knock-in (APP-KI) rat model, the developmental changes of temporal order memory (TOM) and the relationship with medial prefrontal cortex and perirhinal cortex (mPFC-PRH) circuit were determined through in vivo electrophysiology and microimaging technique. We observed a deficit in TOM performance during the object temporal order memory task (OTOMT) in APP-KI rats at 6 month old, which was not evident at 3 or 4 months of age. Alongside behavioral changes, we identified a gradually extensive and aggravated regional activation and functional alterations in the mPFC and PRH during the performance of OTOMT, which occurred prior to the onset of TOM deficits. Moreover, coherence analysis showed that the functional connectivity between the mPFC and PRH could predict the extent of future behavioral performance. Further analysis revealed that the aberrant mPFC-PRH interaction mainly attributed to the progressive deterioration of synaptic transmission, information flow and network coordination from mPFC to PRH, suggesting the mPFC dysfunction maybe the key area of origin underlying the early changes of TOM. These findings identify a pivotal role of the mPFC-PRH circuit in mediating the TOM deficits in the early stage of AD, which holds promising clinical translational value and offers potential early biological markers for predicting AD memory progression.
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Enfermedad de Alzheimer , Corteza Perirrinal , Corteza Prefrontal , Animales , Corteza Prefrontal/fisiopatología , Corteza Perirrinal/fisiología , Enfermedad de Alzheimer/fisiopatología , Ratas , Masculino , Trastornos de la Memoria/fisiopatología , Modelos Animales de Enfermedad , Ratas Transgénicas , Vías Nerviosas/fisiopatología , Memoria EpisódicaRESUMEN
Repeated use of opioid analgesics may cause a paradoxically exacerbated pain known as opioid-induced hyperalgesia (OIH), which hinders effective clinical intervention for severe pain. Currently, little is known about the neural circuits underlying OIH modulation. Previous studies suggest that laterocapsular division of the central nucleus of amygdala (CeLC) is critically involved in the regulation of OIH. Our purpose is to clarify the role of the projections from infralimbic medial prefrontal cortex (IL) to CeLC in OIH. We first produced an OIH model by repeated fentanyl subcutaneous injection in male rats. Immunofluorescence staining revealed that c-Fos-positive neurons were significantly increased in the right CeLC in OIH rats than the saline controls. Then, we used calcium/calmodulin-dependent protein kinase IIα (CaMKIIα) labeling and the patch-clamp recordings with ex vivo optogenetics to detect the functional projections from glutamate pyramidal neurons in IL to the CeLC. The synaptic transmission from IL to CeLC, shown in the excitatory postsynaptic currents (eEPSCs), inhibitory postsynaptic currents (eIPSCs) and paired-pulse ratio (PPR), was observably enhanced after fentanyl administration. Moreover, optogenetic activation of this IL-CeLC pathway decreased c-Fos expression in CeLC and ameliorated mechanical and thermal pain in OIH. On the contrary, silencing this pathway by chemogenetics exacerbated OIH by activating the CeLC. Combined with the electrophysiology results, the enhanced synaptic transmission from IL to CeLC might be a cortical gain of IL to relieve OIH rather than a reason for OIH generation. Scaling up IL outputs to CeLC may be an effective neuromodulation strategy to treat OIH.
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Analgésicos Opioides , Hiperalgesia , Ratas , Masculino , Animales , Hiperalgesia/metabolismo , Analgésicos Opioides/metabolismo , Ratas Sprague-Dawley , Amígdala del Cerebelo/metabolismo , Dolor/metabolismo , Fentanilo , Corteza Prefrontal/metabolismoRESUMEN
Cross-situational inconsistency is common in the expression of honesty traits; yet, there is insufficient emphasis on behavioral dishonesty across multiple contexts. The current study aimed to investigate behavioral dishonesty in various contexts and reveal the associations between trait honesty, behavioral dishonesty, and neural patterns of observing others behave honestly or dishonestly in videos (abbr.: (dis)honesty video-watching). First, the results revealed limitations in using trait honesty to reflect variations in dishonest behaviors and predict behavioral dishonesty. The finding highlights the importance of considering neural patterns in understanding and predicting dishonest behaviors. Second, by comparing the predictive performance of seven types of data across three neural networks, the results showed that functional connectivity in the hypothesis-driven network during (dis)honesty video-watching provided the highest predictive power in predicting multitask behavioral dishonesty. Last, by applying the feature elimination method, the midline self-referential regions (medial prefrontal cortex, posterior cingulate cortex, and anterior cingulate cortex), anterior insula, and striatum were identified as the most informative brain regions in predicting behavioral dishonesty. In summary, the study offered insights into individual differences in deception and the intricate connections among trait honesty, behavioral dishonesty, and neural patterns during (dis)honesty video-watching.
Asunto(s)
Decepción , Imagen por Resonancia Magnética , Red Nerviosa , Humanos , Masculino , Femenino , Adulto , Adulto Joven , Red Nerviosa/fisiología , Red Nerviosa/diagnóstico por imagen , Conectoma , Corteza Cerebral/fisiología , Corteza Cerebral/diagnóstico por imagen , Grabación en Video , Conducta SocialRESUMEN
Corticotropin-releasing hormone (CRH) neurons are densely distributed in the medial prefrontal cortex (mPFC), which plays a crucial role in integrating and processing emotional and cognitive inputs from other brain regions. Therefore, it is important to know the neural afferent patterns of mPFCCRH neurons, which are still unclear. Here, we utilized a rabies virus-based monosynaptic retrograde tracing system to map the presynaptic afferents of the mPFCCRH neurons throughout the entire brain. The results show that the mPFCCRH neurons receive inputs from three main groups of brain regions: (1) the cortex, primarily the orbital cortex, somatomotor areas, and anterior cingulate cortex; (2) the thalamus, primarily the anteromedial nucleus, mediodorsal thalamic nucleus, and central medial thalamic nucleus; and (3) other brain regions, primarily the basolateral amygdala, hippocampus, and dorsal raphe nucleus. Taken together, our results are valuable for further investigations into the roles of the mPFCCRH neurons in normal and neurological disease states. These investigations can shed light on various aspects such as cognitive processing, emotional modulation, motivation, sociability, and pain.