Involvement of prelimbic cortex neurons and related circuits in the acquisition of cooperative learning by pairs of rats

Social behaviors such as cooperation are crucial for mammals. A deeper knowledge of the neuronal mechanisms underlying cooperation can be beneficial for people suffering from pathologies with impaired social behavior. Our aim was to study the brain activity when two animals synchronize their behavior to obtain a mutual reinforcement. In a previous work, we showed that the activity of the prelimbic cortex (PrL) was enhanced during cooperation in rats, especially in the ones leading most cooperative trials (leader rats). In this study, we investigated the specific cell type/s in the PrL contributing to cooperative behaviors. To this end, we collected rats' brains at key moments of the learning process to analyze the levels of c-FOS expression in the main cellular groups of the PrL (glutamatergic cells containing D1 and D2 receptors and interneurons). Leader rats showed increased c-FOS activity in cells expressing D1 receptors during cooperation. In addition, we analyzed the levels of anxiety, dominance, and locomotor behavior, finding that leader rats are in general less anxious and less dominant than followers. We also recorded local field potentials (LFPs) from the PrL, the nucleus accumbens septi (NAc), and the basolateral amygdala (BLA). Spectral analysis showed that delta activity in PrL and NAc increased when rats cooperated, while BLA activity in delta and theta bands decreased considerably during cooperation. The PrL and NAc also increased their connectivity in the high theta band during cooperation. Thus, the present work identifies the specific PrL cell types engaged in this behavior, as well as its connectivity with subcortical brain regions (BLA, NAc) during cooperation.

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Hippocampal and thalamic afferents form distinct synaptic microcircuits in the mouse frontal cortex

10.1101/2021.03.12.435140 ◽

2021 ◽

Author(s):

Kourtney Graham ◽

Nelson Spruston ◽

Erik B. Bloss

Keyword(s):

Information Processing ◽

Frontal Cortex ◽

Cortical Neurons ◽

Basolateral Amygdala ◽

Cell Types ◽

Brain Regions ◽

Projection Neurons ◽

Specific Cell ◽

Nucleus Reuniens ◽

Level Information

AbstractNeural circuits within the frontal cortex support the flexible selection of goal-directed behaviors by integrating input from brain regions associated with sensory, emotional, episodic, and semantic memory functions. From a connectomics perspective, determining how these disparate afferent inputs target their synapses to specific cell types in the frontal cortex may prove crucial in understanding circuit-level information processing. Here, we used monosynaptic retrograde rabies mapping to examine the distribution of afferent neurons targeting four distinct classes of local inhibitory interneurons and four distinct classes of excitatory projection neurons in mouse infralimbic cortex. Interneurons expressing parvalbumin, somatostatin, or vasoactive intestinal peptide received a large proportion of inputs from hippocampal regions, while interneurons expressing neuron-derived neurotrophic factor received a large proportion of inputs from thalamic regions. A more moderate hippocampal-thalamic dichotomy was found among the inputs targeting excitatory neurons that project to the basolateral amygdala, lateral entorhinal cortex, nucleus reuniens of the thalamus, and the periaqueductal gray. Together, these results show a prominent bias among hippocampal and thalamic afferent systems in their targeting to genetically or anatomically defined sets of frontal cortical neurons. Moreover, they suggest the presence of two distinct local microcircuits that control how different inputs govern frontal cortical information processing.

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Convergence Circuit Mapping: Genetic Approaches From Structure to Function

Frontiers in Systems Neuroscience ◽

10.3389/fnsys.2021.688673 ◽

2021 ◽

Vol 15 ◽

Author(s):

Jang Soo Yook ◽

Jihyun Kim ◽

Jinhyun Kim

Keyword(s):

Fluorescent Proteins ◽

Brain Activity ◽

Molecular Genetic ◽

Cell Types ◽

Brain Regions ◽

Genetically Engineered ◽

Spatiotemporal Resolution ◽

Genetic Switches ◽

A Cell ◽

And Behavior

Understanding the complex neural circuits that underpin brain function and behavior has been a long-standing goal of neuroscience. Yet this is no small feat considering the interconnectedness of neurons and other cell types, both within and across brain regions. In this review, we describe recent advances in mouse molecular genetic engineering that can be used to integrate information on brain activity and structure at regional, cellular, and subcellular levels. The convergence of structural inputs can be mapped throughout the brain in a cell type-specific manner by antero- and retrograde viral systems expressing various fluorescent proteins and genetic switches. Furthermore, neural activity can be manipulated using opto- and chemo-genetic tools to interrogate the functional significance of this input convergence. Monitoring neuronal activity is obtained with precise spatiotemporal resolution using genetically encoded sensors for calcium changes and specific neurotransmitters. Combining these genetically engineered mapping tools is a compelling approach for unraveling the structural and functional brain architecture of complex behaviors and malfunctioned states of neurological disorders.

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MRI of Capn15 knockout mice and analysis of Capn15 distribution reveal possible roles in brain development and plasticity

10.1101/763888 ◽

2019 ◽

Cited By ~ 1

Author(s):

Congyao Zha ◽

Carole A Farah ◽

Vladimir Fonov ◽

David A. Rudko ◽

Wayne S Sossin

Keyword(s):

Brain Development ◽

Knockout Mice ◽

Brain Plasticity ◽

Small Animal ◽

Cell Types ◽

Cysteine Proteases ◽

Brain Regions ◽

Conditional Knockout ◽

Specific Cell ◽

The Brain

AbstractPurposeThe non-classical Small Optic Lobe (SOL) family of calpains are intracellular cysteine proteases that are expressed in the nervous system and appear to play an important role in neuronal development in both Drosophila, where loss of this calpain leads to the eponymous small optic lobes, and in mouse and human, where loss of this calpain (Capn15) leads to eye anomalies. However, the brain regions where this calpain is expressed and the areas most affected by the loss of this calpain have not been carefully examined.ProceduresWe utilize an insert strain where lacZ is expressed under the control of the Capn15 promoter, together with immunocytochemistry with markers of specific cell types to address where Capn 15 is expressed in the brain. We use small animal MRI comparing WT, Capn15 knockout and Capn15 conditional knockout mice to address the brain regions that are affected when Capn 15 is not present, either in early development of the adult.ResultsCapn15 is expressed in diverse brain regions, many of them involved in plasticity such as the hippocampus, lateral amygdala and Purkinje neurons. Capn15 knockout mice have smaller brains, and present specific deficits in the thalamus and hippocampal regions. There are no deficits revealed by MRI in brain regions when Capn15 is knocked out after development.ConclusionsAreas where Capn15 is expressed in the adult are not good markers for the specific regions where the loss of Capn15 specifically affects brain development. Thus, it is likely that this calpain plays distinct roles in brain development and brain plasticity.

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Glucocorticoid enhancement of recognition memory via basolateral amygdala-driven facilitation of prelimbic cortex interactions

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1901513116 ◽

2019 ◽

Vol 116 (14) ◽

pp. 7077-7082 ◽

Cited By ~ 9

Author(s):

Areg Barsegyan ◽

Gabriele Mirone ◽

Giacomo Ronzoni ◽

Chunan Guo ◽

Qi Song ◽

...

Keyword(s):

Object Recognition ◽

Recognition Memory ◽

Memory Consolidation ◽

Basolateral Amygdala ◽

Emotional Arousal ◽

Brain Regions ◽

Prelimbic Cortex ◽

Stress Hormone ◽

Functional Connections ◽

Functional Interactions

Extensive evidence indicates that the basolateral amygdala (BLA) interacts with other brain regions in mediating stress hormone and emotional arousal effects on memory consolidation. Brain activation studies have shown that arousing conditions lead to the activation of large-scale neural networks and several functional connections between brain regions beyond the BLA. Whether such distal interactions on memory consolidation also depend on BLA activity is not as yet known. We investigated, in male Sprague–Dawley rats, whether BLA activity enables prelimbic cortex (PrL) interactions with the anterior insular cortex (aIC) and dorsal hippocampus (dHPC) in regulating glucocorticoid effects on different components of object recognition memory. The glucocorticoid receptor (GR) agonist RU 28362 administered into the PrL, but not infralimbic cortex, immediately after object recognition training enhanced 24-hour memory of both the identity and location of the object via functional interactions with the aIC and dHPC, respectively. Importantly, posttraining inactivation of the BLA by the noradrenergic antagonist propranolol abolished the effect of GR agonist administration into the PrL on memory enhancement of both the identity and location of the object. BLA inactivation by propranolol also blocked the effect of GR agonist administration into the PrL on inducing changes in neuronal activity within the aIC and dHPC during the postlearning consolidation period as well as on structural changes in spine morphology assessed 24 hours later. These findings provide evidence that BLA noradrenergic activity enables functional interactions between the PrL and the aIC and dHPC in regulating stress hormone and emotional arousal effects on memory.

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Effect of the aerobic exercise and the environmental enrichment on the reduction of the anxiety levels in the aging

European Journal of Investigation in Health, Psychology and Education ◽

10.3390/ejihpe5020019 ◽

2015 ◽

Vol 5 (2) ◽

pp. 197-208

Author(s):

Patricia Sampedro

Keyword(s):

Aerobic Exercise ◽

Hpa Axis ◽

Environmental Enrichment ◽

Basolateral Amygdala ◽

Dorsal Hippocampus ◽

Brain Activity ◽

Brain Regions ◽

Bed Nucleus ◽

Hypothalamic Pituitary Axis ◽

Anxiety Levels

The environmental enrichment (EE) and the aerobic exercise (EX) are interventions capable of reducing anxiety levels in the aging, but few is known about how they modulating the projections to the hypothalamic-pituitary axis (HPA). We studied the effect of an EE and EX programs carried out during two months in 18 month-old Wistar rats assigned to 3 groups: (CO, N=6), EE (N=8) y EX (N=8). The EX program was carried out during 15min/day and the EE group was housed in a big cage with different objects frequently changed. Through the cytochrome c oxidase histochemistry (COx), we analysed the metabolic activity of several brain regions involved in the anxiety response. The EE reduced the brain activity of regions involved in the activation of the HPA axis (infralimbic cortex, basolateral amygdala and the hypothalamic paraventricular nucleus (p<0.05). On the other hand, the EX program increased the activity of brain regions involved in the inhibition of the HPA axis (cingulate cortex, bed nucleus of the stria terminalis and the dorsal hippocampus (p<0.05). In conclusion, it seemed that the EE and the EX modulate in different way the activity of brain regions that project to the HPA axis and they could constitute successful interventions to reduce the anxiety levels in the aging.

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Cell-type, single-cell, and spatial signatures of brain-region specific splicing in postnatal development

10.1101/2020.08.27.268730 ◽

2020 ◽

Cited By ~ 1

Author(s):

Anoushka Joglekar ◽

Andrey Prjibelski ◽

Ahmed Mahfouz ◽

Paul Collier ◽

Susan Lin ◽

...

Keyword(s):

Single Cell ◽

Brain Region ◽

Cell Types ◽

Brain Regions ◽

Specific Cell ◽

Cell Type ◽

Anatomic Structure ◽

Link Type ◽

Long Read ◽

Isoform Expression

AbstractAlternative RNA splicing varies across brain regions, but the single-cell resolution of such regional variation is unknown. Here we present the first single-cell investigation of differential isoform expression (DIE) between brain regions, by performing single cell long-read transcriptome sequencing in the mouse hippocampus and prefrontal cortex in 45 cell types at postnatal day 7 (www.isoformAtlas.com). Using isoform tests for brain-region specific DIE, which outperform exon-based tests, we detect hundreds of brain-region specific DIE events traceable to specific cell-types. Many DIE events correspond to functionally distinct protein isoforms, some with just a 6-nucleotide exon variant. In most instances, one cell type is responsible for brain-region specific DIE. Cell types indigenous to only one anatomic structure display distinctive DIE, where for example, the choroid plexus epithelium manifest unique transcription start sites. However, for some genes, multiple cell-types are responsible for DIE in bulk data, indicating that regional identity can, although less frequently, override cell-type specificity. We validated our findings with spatial transcriptomics and long-read sequencing, yielding the first spatially resolved splicing map in the postnatal mouse brain (www.isoformAtlas.com). Our methods are highly generalizable. They provide a robust means of quantifying isoform expression with cell-type and spatial resolution, and reveal how the brain integrates molecular and cellular complexity to serve function.

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GWAS Meta-Analysis of Neuroticism (N=449,484) Identifies Novel Genetic Loci and Pathways

10.1101/184820 ◽

2017 ◽

Cited By ~ 8

Author(s):

Mats Nagel ◽

Philip R Jansen ◽

Sven Stringer ◽

Kyoko Watanabe ◽

Christiaan A de Leeuw ◽

...

Keyword(s):

Association Studies ◽

Meta Analysis ◽

Cell Types ◽

Brain Regions ◽

Specific Cell ◽

Medium Spiny Neurons ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Genetic Signal

Neuroticism is an important risk factor for psychiatric traits including depression1, anxiety2,3, and schizophrenia4–6. Previous genome-wide association studies7–12 (GWAS) reported 16 genomic loci10–12. Here we report the largest neuroticism GWAS meta-analysis to date (N=449,484), and identify 136 independent genome-wide significant loci (124 novel), implicating 599 genes. Extensive functional follow-up analyses show enrichment in several brain regions and involvement of specific cell-types, including dopaminergic neuroblasts (P=3×10-8), medium spiny neurons (P=4×10-8) and serotonergic neurons (P=1×10-7). Gene-set analyses implicate three specific pathways: neurogenesis (P=4.4×10-9), behavioural response to cocaine processes (P=1.84×10-7), and axon part (P=5.26×10-8). We show that neuroticism’s genetic signal partly originates in two genetically distinguishable subclusters13 (depressed affect and worry, the former being genetically strongly related to depression, rg=0.84), suggesting distinct causal mechanisms for subtypes of individuals. These results vastly enhance our neurobiological understanding of neuroticism, and provide specific leads for functional follow-up experiments.

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Single-nuclei transcriptomics of schizophrenia prefrontal cortex primarily implicates neuronal subtypes

10.1101/2020.07.29.227355 ◽

2020 ◽

Author(s):

Benjamin C. Reiner ◽

Richard C. Crist ◽

Lauren M. Stein ◽

Andrew E. Weller ◽

Glenn A. Doyle ◽

...

Keyword(s):

Prefrontal Cortex ◽

Differentially Expressed Genes ◽

Neuronal Cell ◽

Cell Types ◽

Brain Regions ◽

Differentially Expressed ◽

Inhibitory Neurons ◽

Specific Cell ◽

Dorsolateral Prefrontal ◽

Layer V

AbstractTranscriptomic studies of bulk neural tissue homogenates from persons with schizophrenia and controls have identified differentially expressed genes in multiple brain regions. However, the heterogeneous nature prevents identification of relevant cell types. This study analyzed single-nuclei transcriptomics of ∼311,000 nuclei from frozen human postmortem dorsolateral prefrontal cortex samples from individuals with schizophrenia (n = 14) and controls (n = 16). 2,846 differential expression events were identified in 2,195 unique genes in 19 of 24 transcriptomically-distinct cell populations. ∼97% of differentially expressed genes occurred in five neuronal cell types, with ∼63% occurring in a subtype of PVALB+ inhibitory neurons and HTR2C+ layer V excitatory neurons. Differentially expressed genes were enriched for genes localized to schizophrenia GWAS loci. Cluster-specific changes in canonical pathways, upstream regulators and causal networks were identified. These results expand our knowledge of disrupted gene expression in specific cell types and permit new insight into the pathophysiology of schizophrenia.

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Cell-Type-Specific Proteomics: A Neuroscience Perspective

Proteomes ◽

10.3390/proteomes6040051 ◽

2018 ◽

Vol 6 (4) ◽

pp. 51 ◽

Cited By ~ 7

Author(s):

Rashaun S. Wilson ◽

Angus C. Nairn

Keyword(s):

Protein Detection ◽

Analytical Techniques ◽

Cell Types ◽

Brain Regions ◽

Cell Populations ◽

Specific Cell ◽

Cell Type ◽

Specific Analysis ◽

Cell Type Specific ◽

Proteomics Research

Cell-type-specific analysis has become a major focus for many investigators in the field of neuroscience, particularly because of the large number of different cell populations found in brain tissue that play roles in a variety of developmental and behavioral disorders. However, isolation of these specific cell types can be challenging due to their nonuniformity and complex projections to different brain regions. Moreover, many analytical techniques used for protein detection and quantitation remain insensitive to the low amounts of protein extracted from specific cell populations. Despite these challenges, methods to improve proteomic yield and increase resolution continue to develop at a rapid rate. In this review, we highlight the importance of cell-type-specific proteomics in neuroscience and the technical difficulties associated. Furthermore, current progress and technological advancements in cell-type-specific proteomics research are discussed with an emphasis in neuroscience.

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Identification of 13 independent genetic loci associated with cognitive resilience in healthy aging in 330,097 individuals in the UK Biobank

10.1101/2021.01.22.427640 ◽

2021 ◽

Author(s):

Joan Fitzgerald ◽

Laura Fahey ◽

Laurena Holleran ◽

Pilib Ó Broin ◽

Gary Donohoe ◽

...

Keyword(s):

Healthy Aging ◽

Genome Wide Association Study ◽

Cell Types ◽

Brain Regions ◽

Specific Cell ◽

Uk Biobank ◽

Negative Effects ◽

Genome Wide ◽

A Genome ◽

The Uk

AbstractCognitive resilience is the ability to withstand the negative effects of stress on cognitive functioning and is important for maintaining quality of life while aging. Here we employed a proxy phenotype approach to create a longitudinal cognitive resilience phenotype using past education years and current processing speed, reflecting an average time span of 40 years, in 330,097 individuals from the UK Biobank. A genome-wide association study identified 13 independent genome-wide significant loci that implicate 33 genes. A portion of resilience’s genetic signal is distinct from the genetics of intelligence. Functional analyses showed enrichment in several brain regions and involvement of specific cell types, including GABAergic neurons (P=6.59×10−8) and glutamatergic neurons (P=6.98×10−6) in the cortex. Gene-set analyses implicated the biological process “neuron differentiation” (P=9.7×10−7) and the cellular component “synaptic part” (P=2.14×10−6). Mendelian randomization analysis showed a causative effect of white matter volume on cognitive resilience. These results enhance neurobiological understanding of resilience.

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