Periodic Reporting for period 2 - CLAUSTROFUNCT (Claustrum function in cortical processing and putative claustral dysfunction in schizophrenia)
Période du rapport: 2021-12-01 au 2023-05-31
Schizophrenia is a chronic mental disease having an incidence of 1% worldwide, all continents exhibiting similar rates. Though the disorder is slightly more often observed in males than females (ratio 1 to 1.4) the age onset is usually earlier and the intensity of symptoms is stronger in males. This psychiatric disorder is characterized by positive and negative symptoms as well as cognitive deficits. Positive symptoms, which are the most striking manifestations, include hallucinations, delusions, confused speech and false beliefs. The negative symptoms represent a reduction of emotional responsiveness, motivation and socialization whereas cognitive deficits denote altered memory and altered executive functions. Though current antipsychotic drugs usually alleviate positive symptoms, they are much less efficient to treat negative and cognitive ones. The latter symptoms remain thus a major burden for the patients, strongly affecting their quality of life. It is therefore important to better characterize the neural circuits involved in negative and cognitive symptoms and study their potential dysfunction in the pathology.
Although the exact causes of schizophrenia are not known, several works suggest that impaired communication between higher brain centers may be important for the expression of the disease. For example, data collected both in human patients and mouse models of the disorder support the view that communication between the prefrontal cortex and other circuits such as the hippocampus are altered. Over the last decade, rodents have been used to study behavioral traits relevant to the various symptoms observed in the pathology. Animal research thus represents a critical tool to establish a causal link between circuit function (and/or dysfunction) and particular behavioral traits relevant to schizophrenia, which may shed new light on the mechanisms underlying the pathology.
The claustrum CLA represents a subcortical structure highly reciprocally interconnected with the neocortex and in particular with various associative cortices involved in behavioral traits relevant to schizophrenia. Our project aims at testing the hypothesis that the claustrum may be an important network contributing to circuit dysfunction and abnormal behavior relevant to schizophrenia. We propose to study the existence of a causal link between manipulation of claustrum neuron activity in mice and altered behavior relevant to schizophrenia.
Although the exact causes of schizophrenia are not known, several works suggest that impaired communication between higher brain centers may be important for the expression of the disease. For example, data collected both in human patients and mouse models of the disorder support the view that communication between the prefrontal cortex and other circuits such as the hippocampus are altered. Over the last decade, rodents have been used to study behavioral traits relevant to the various symptoms observed in the pathology. Animal research thus represents a critical tool to establish a causal link between circuit function (and/or dysfunction) and particular behavioral traits relevant to schizophrenia, which may shed new light on the mechanisms underlying the pathology.
The claustrum CLA represents a subcortical structure highly reciprocally interconnected with the neocortex and in particular with various associative cortices involved in behavioral traits relevant to schizophrenia. Our project aims at testing the hypothesis that the claustrum may be an important network contributing to circuit dysfunction and abnormal behavior relevant to schizophrenia. We propose to study the existence of a causal link between manipulation of claustrum neuron activity in mice and altered behavior relevant to schizophrenia.
Cognitive dysfunctions, which are a hallmark of many psychiatric conditions including schizophrenia and attention-deficit hyperactivity disorder (ADHD), represent a major burden in the daily life of patients. It is particularly true since current medications poorly alleviate this class of symptoms. Therefore, a better understanding of the brain circuits involved in cognitive functions and/or dysfunctions is critical to better handle psychiatric pathologies and develop new therapies. Prefrontal cortex (PFC) regions have long been recognized as a neuronal hub contributing to various cognitive functions such as planning, attentional processes and working memory. The current study investigates how the claustrum (CLA) may participate in these cognitive insufficiencies.
The CLA remains one of the most enigmatic neuronal network in the brain. Although it was shown anatomically to share dense reciprocal connections with the neocortex, this network has rarely been studied because of its location and the difficulty to specifically manipulate its neurons without altering the activity of neighboring brain areas.
In this study, we molecularly distinguished CLA neurons from neighboring striatal and insular cortical neurons from adult brains using single cell RNA sequencing (scRNAseq). We identified a single neuronal population expressing all previously identified CLA marker genes. We used a transgenic mouse in which a Cre recombinase was specifically expressed in CLA glutamatergic neurons. Using conditional viral tracing and optogenetics, we studied the axonal projections originating from CLA neurons and demonstrated that the frontal cortex receives strong claustral inputs, which increase the excitability of pyramidal neurons both in vitro and in vivo.
Frontal regions being implicated in executive functions, we tested whether CLA neurons might be involved in cognitive flexibility and attention. Using microendoscopic calcium imaging, we monitored the activity evoked either in the CLA or in the medial prefrontal cortex (mPFC) during an attentional set-shifting task. In both networks, specific ensembles of neurons were activated during the task and displayed learning-dependent remapping. Specific CLA chemogenetic inhibition prevented the formation of reliable mPFC assemblies specifically during attentional set-shifting. These mice were concomitantly unable to shift their attention, phenocopying the consequence of mPFC lesions described in the literature, and a particular phenotype observed in schizophrenia (as well as in mouse models of this pathology). Mice were also unable to shift their attention when the formation of specific CLA cell assemblies was perturbed by optogenetic stimulation.
The CLA remains one of the most enigmatic neuronal network in the brain. Although it was shown anatomically to share dense reciprocal connections with the neocortex, this network has rarely been studied because of its location and the difficulty to specifically manipulate its neurons without altering the activity of neighboring brain areas.
In this study, we molecularly distinguished CLA neurons from neighboring striatal and insular cortical neurons from adult brains using single cell RNA sequencing (scRNAseq). We identified a single neuronal population expressing all previously identified CLA marker genes. We used a transgenic mouse in which a Cre recombinase was specifically expressed in CLA glutamatergic neurons. Using conditional viral tracing and optogenetics, we studied the axonal projections originating from CLA neurons and demonstrated that the frontal cortex receives strong claustral inputs, which increase the excitability of pyramidal neurons both in vitro and in vivo.
Frontal regions being implicated in executive functions, we tested whether CLA neurons might be involved in cognitive flexibility and attention. Using microendoscopic calcium imaging, we monitored the activity evoked either in the CLA or in the medial prefrontal cortex (mPFC) during an attentional set-shifting task. In both networks, specific ensembles of neurons were activated during the task and displayed learning-dependent remapping. Specific CLA chemogenetic inhibition prevented the formation of reliable mPFC assemblies specifically during attentional set-shifting. These mice were concomitantly unable to shift their attention, phenocopying the consequence of mPFC lesions described in the literature, and a particular phenotype observed in schizophrenia (as well as in mouse models of this pathology). Mice were also unable to shift their attention when the formation of specific CLA cell assemblies was perturbed by optogenetic stimulation.
We propose that CLA ensembles are activated during cognitive tasks and drive the reorganization of mPFC ensembles to promote cognitive flexibility, which emphasizes the potential role played by the CLA in executive dysfunctions, in particular in attentional deficits observed in neuropathologies such as schizophrenia and ADHD.
We will test the potential dysfunction of CLA neurons in animal models of psychiatric disorders.
We will test the potential dysfunction of CLA neurons in animal models of psychiatric disorders.