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Cell Sep 2023Social preference, the decision to interact with one member of the same species over another, is critical to optimize social interactions. Thus, adult rodents favor...
Social preference, the decision to interact with one member of the same species over another, is critical to optimize social interactions. Thus, adult rodents favor interacting with novel conspecifics over familiar ones, but whether this social preference stems from neural circuits facilitating interactions with novel individuals or suppressing interactions with familiar ones remains unknown. Here, we identify neurons in the infra-limbic area (ILA) of the mouse prefrontal cortex that express the neuropeptide corticotropin-releasing hormone (CRH) and project to the dorsal region of the rostral lateral septum (rLS). We show how release of CRH during familiar encounters disinhibits rLS neurons, thereby suppressing social interactions with familiar mice and contributing to social novelty preference. We further demonstrate how the maturation of CRH expression in ILA during the first 2 post-natal weeks enables the developmental shift from a preference for littermates in juveniles to a preference for novel mice in adults.
Topics: Animals; Mice; Corticotropin-Releasing Hormone; Neurons; Prefrontal Cortex; Signal Transduction; Perception
PubMed: 37669667
DOI: 10.1016/j.cell.2023.08.010 -
Annals of the New York Academy of... Jul 2023A functional interplay of bottom-up and top-down processing allows an individual to appropriately respond to the dynamic environment around them. These processing... (Review)
Review
A functional interplay of bottom-up and top-down processing allows an individual to appropriately respond to the dynamic environment around them. These processing modalities can be represented as attractor states using a dynamical systems model of the brain. The transition probability to move from one attractor state to another is dependent on the stability, depth, neuromodulatory tone, and tonic changes in plasticity. However, how does the relationship between these states change in disease states, such as anxiety or depression? We describe bottom-up and top-down processing from Marr's computational-algorithmic-implementation perspective to understand depressive and anxious disease states. We illustrate examples of bottom-up processing as basolateral amygdala signaling and projections and top-down processing as medial prefrontal cortex internal signaling and projections. Understanding these internal processing dynamics can help us better model the multifaceted elements of anxiety and depression.
Topics: Humans; Depression; Brain Mapping; Anxiety; Brain; Anxiety Disorders; Prefrontal Cortex
PubMed: 37129246
DOI: 10.1111/nyas.14997 -
Nature Mar 2024Astrocytes are heterogeneous glial cells of the central nervous system. However, the physiological relevance of astrocyte diversity for neural circuits and behaviour...
Astrocytes are heterogeneous glial cells of the central nervous system. However, the physiological relevance of astrocyte diversity for neural circuits and behaviour remains unclear. Here we show that a specific population of astrocytes in the central striatum expresses μ-crystallin (encoded by Crym in mice and CRYM in humans) that is associated with several human diseases, including neuropsychiatric disorders. In adult mice, reducing the levels of μ-crystallin in striatal astrocytes through CRISPR-Cas9-mediated knockout of Crym resulted in perseverative behaviours, increased fast synaptic excitation in medium spiny neurons and dysfunctional excitatory-inhibitory synaptic balance. Increased perseveration stemmed from the loss of astrocyte-gated control of neurotransmitter release from presynaptic terminals of orbitofrontal cortex-striatum projections. We found that perseveration could be remedied using presynaptic inhibitory chemogenetics, and that this treatment also corrected the synaptic deficits. Together, our findings reveal converging molecular, synaptic, circuit and behavioural mechanisms by which a molecularly defined and allocated population of striatal astrocytes gates perseveration phenotypes that accompany neuropsychiatric disorders. Our data show that Crym-positive striatal astrocytes have key biological functions within the central nervous system, and uncover astrocyte-neuron interaction mechanisms that could be targeted in treatments for perseveration.
Topics: Animals; Humans; Mice; Astrocytes; Corpus Striatum; Gene Editing; Gene Knockout Techniques; mu-Crystallins; Rumination, Cognitive; Synaptic Transmission; CRISPR-Cas Systems; Medium Spiny Neurons; Synapses; Prefrontal Cortex; Presynaptic Terminals; Neural Inhibition
PubMed: 38418885
DOI: 10.1038/s41586-024-07138-0 -
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 -
Molecular Psychiatry Nov 2023Reductions of astroglia expressing glial fibrillary acidic protein (GFAP) are consistently found in the prefrontal cortex (PFC) of patients with depression and in rodent...
Reductions of astroglia expressing glial fibrillary acidic protein (GFAP) are consistently found in the prefrontal cortex (PFC) of patients with depression and in rodent chronic stress models. Here, we examine the consequences of PFC GFAP+ cell depletion and cell activity enhancement on depressive-like behaviors in rodents. Using viral expression of diphtheria toxin receptor in PFC GFAP+ cells, which allows experimental depletion of these cells following diphtheria toxin administration, we demonstrated that PFC GFAP+ cell depletion induced anhedonia-like behavior within 2 days and lasting up to 8 days, but no anxiety-like deficits. Conversely, activating PFC GFAP+ cell activity for 3 weeks using designer receptor exclusively activated by designer drugs (DREADDs) reversed chronic restraint stress-induced anhedonia-like deficits, but not anxiety-like deficits. Our results highlight a critical role of cortical astroglia in the development of anhedonia and further support the idea of targeting astroglia for the treatment of depression.
Topics: Animals; Humans; Astrocytes; Anhedonia; Prefrontal Cortex; Depression; Stress, Psychological; Behavior, Animal
PubMed: 37696873
DOI: 10.1038/s41380-023-02246-1 -
Nature Neuroscience Nov 2023The prefrontal cortex (PFC) is a complex brain region that regulates diverse functions ranging from cognition, emotion and executive action to even pain processing. To...
The prefrontal cortex (PFC) is a complex brain region that regulates diverse functions ranging from cognition, emotion and executive action to even pain processing. To decode the cellular and circuit organization of such diverse functions, we employed spatially resolved single-cell transcriptome profiling of the adult mouse PFC. Results revealed that PFC has distinct cell-type composition and gene-expression patterns relative to neighboring cortical areas-with neuronal excitability-regulating genes differently expressed. These cellular and molecular features are further segregated within PFC subregions, alluding to the subregion-specificity of several PFC functions. PFC projects to major subcortical targets through combinations of neuronal subtypes, which emerge in a target-intrinsic fashion. Finally, based on these features, we identified distinct cell types and circuits in PFC underlying chronic pain, an escalating healthcare challenge with limited molecular understanding. Collectively, this comprehensive map will facilitate decoding of discrete molecular, cellular and circuit mechanisms underlying specific PFC functions in health and disease.
Topics: Mice; Animals; Transcriptome; Chronic Pain; Cognition; Prefrontal Cortex; Gene Expression Profiling
PubMed: 37845544
DOI: 10.1038/s41593-023-01455-9 -
Schizophrenia Bulletin Nov 2023The neurocomputational framework of predictive processing (PP) provides a promising approach to explaining delusions, a key symptom of psychotic disorders. According to... (Review)
Review
BACKGROUND AND HYPOTHESIS
The neurocomputational framework of predictive processing (PP) provides a promising approach to explaining delusions, a key symptom of psychotic disorders. According to PP, the brain makes inferences about the world by weighing prior beliefs against the available sensory data. Mismatches between prior beliefs and sensory data result in prediction errors that may update the brain's model of the world. Psychosis has been associated with reduced weighting of priors relative to the sensory data. However, delusional beliefs are highly resistant to change, suggesting increased rather than decreased weighting of priors. We propose that this "delusion paradox" can be resolved within a hierarchical PP model: Reduced weighting of prior beliefs at low hierarchical levels may be compensated by an increased influence of higher-order beliefs represented at high hierarchical levels, including delusional beliefs. This may sculpt perceptual processing into conformity with delusions and foster their resistance to contradictory evidence.
STUDY DESIGN
We review several lines of experimental evidence on low- and high-level processes, and their neurocognitive underpinnings in delusion-related phenotypes and link them to predicted processing.
STUDY RESULTS
The reviewed evidence supports the notion of decreased weighting of low-level priors and increased weighting of high-level priors, in both delusional and delusion-prone individuals. Moreover, we highlight the role of prefrontal cortex as a neural basis for the increased weighting of high-level prior beliefs and discuss possible clinical implications of the proposed hierarchical predictive-processing model.
CONCLUSIONS
Our review suggests the delusion paradox can be resolved within a hierarchical PP model.
Topics: Humans; Delusions; Psychotic Disorders; Brain; Prefrontal Cortex
PubMed: 37478890
DOI: 10.1093/schbul/sbad084 -
Nature Communications Apr 2024Chronic stress induces anxiety disorders via both neural pathways and circulating factors. Although many studies have elucidated the neural circuits involved in...
Chronic stress induces anxiety disorders via both neural pathways and circulating factors. Although many studies have elucidated the neural circuits involved in stress-coping behaviors, the origin and regulatory mechanism of peripheral cytokines in behavioural regulation under stress conditions are not fully understood. Here, we identified a serum cytokine, lipocalin 2 (LCN2), that was upregulated in participants with anxiety disorders. Using a mouse model of chronic restraint stress (CRS), circulating LCN2 was found to be related to stress-induced anxiety-like behaviour via modulation of neural activity in the medial prefrontal cortex (mPFC). These results suggest that stress increases hepatic LCN2 via a neural pathway, leading to disrupted cortical functions and behaviour.
Topics: Humans; Lipocalin-2; Prefrontal Cortex; Anxiety; Anxiety Disorders; Liver
PubMed: 38589429
DOI: 10.1038/s41467-024-47266-9 -
Nature Neuroscience Mar 2024The prefrontal cortex is crucial for learning and decision-making. Classic reinforcement learning (RL) theories center on learning the expectation of potential rewarding...
The prefrontal cortex is crucial for learning and decision-making. Classic reinforcement learning (RL) theories center on learning the expectation of potential rewarding outcomes and explain a wealth of neural data in the prefrontal cortex. Distributional RL, on the other hand, learns the full distribution of rewarding outcomes and better explains dopamine responses. In the present study, we show that distributional RL also better explains macaque anterior cingulate cortex neuronal responses, suggesting that it is a common mechanism for reward-guided learning.
Topics: Animals; Reinforcement, Psychology; Learning; Reward; Prefrontal Cortex; Neurons; Macaca; Decision Making
PubMed: 38200183
DOI: 10.1038/s41593-023-01535-w -
Nature Neuroscience Dec 2023The meta-reinforcement learning (meta-RL) framework, which involves RL over multiple timescales, has been successful in training deep RL models that generalize to new...
The meta-reinforcement learning (meta-RL) framework, which involves RL over multiple timescales, has been successful in training deep RL models that generalize to new environments. It has been hypothesized that the prefrontal cortex may mediate meta-RL in the brain, but the evidence is scarce. Here we show that the orbitofrontal cortex (OFC) mediates meta-RL. We trained mice and deep RL models on a probabilistic reversal learning task across sessions during which they improved their trial-by-trial RL policy through meta-learning. Ca/calmodulin-dependent protein kinase II-dependent synaptic plasticity in OFC was necessary for this meta-learning but not for the within-session trial-by-trial RL in experts. After meta-learning, OFC activity robustly encoded value signals, and OFC inactivation impaired the RL behaviors. Longitudinal tracking of OFC activity revealed that meta-learning gradually shapes population value coding to guide the ongoing behavioral policy. Our results indicate that two distinct RL algorithms with distinct neural mechanisms and timescales coexist in OFC to support adaptive decision-making.
Topics: Mice; Animals; Reward; Reinforcement, Psychology; Prefrontal Cortex; Reversal Learning
PubMed: 37957318
DOI: 10.1038/s41593-023-01485-3