Loss of mGlu5 receptors in somatostatin-expressing neurons alters negative emotional states.

Subtype 5 metabotropic glutamate receptors (mGlu5) are known to play an important role in regulating cognitive, social and valence systems. However, it remains largely unknown at which circuits and neuronal types mGlu5 act to influence these behavioral domains. Altered tissue- or cell-specific expression or function of mGlu5 has been proposed to contribute to the exacerbation of neuropsychiatric disorders. Here, we examined how these receptors regulate the activity of somatostatin-expressing (SST+) neurons, as well as their influence on behavior and brain rhythmic activity. Loss of mGlu5 in SST+ neurons elicited excitatory synaptic dysfunction in a region and sex-specific manner together with a range of emotional imbalances including diminished social novelty preference, reduced anxiety-like behavior and decreased freezing during retrieval of fear memories. In addition, the absence of mGlu5 in SST+ neurons during fear processing impaired theta frequency oscillatory activity in the medial prefrontal cortex and ventral hippocampus. These findings reveal a critical role of mGlu5 in controlling SST+ neurons excitability necessary for regulating negative emotional states.

The role of subicular VIP-expressing interneurons on seizure dynamics in the intrahippocampal kainic acid model of temporal lobe epilepsy.

The subiculum, a key output region of the hippocampus, is increasingly recognized as playing a crucial role in seizure initiation and spread. The subiculum consists of glutamatergic pyramidal cells, which show alterations in intrinsic excitability in the course of epilepsy, and multiple types of GABAergic interneurons, which exhibit varying characteristics in epilepsy. In this study, we aimed to assess the role of the vasoactive intestinal peptide interneurons (VIP-INs) of the ventral subiculum in the pathophysiology of temporal lobe epilepsy. We observed that an anatomically restricted inhibition of VIP-INs of the ventral subiculum was sufficient to reduce seizures in the intrahippocampal kainic acid model of epilepsy, changing the circadian rhythm of seizures, emphasizing the critical role of this small cell population in modulating TLE. As we expected, permanent unilateral or bilateral silencing of VIP-INs of the ventral subiculum in non-epileptic animals did not induce seizures or epileptiform activity. Interestingly, transient activation of VIP-INs of the ventral subiculum was enough to increase the frequency of seizures in the acute seizure model. Our results offer new perspectives on the crucial involvement of VIP-INs of the ventral subiculum in the pathophysiology of TLE. Given the observed predominant disinhibitory role of the VIP-INs input in subicular microcircuits, modifications of this input could be considered in the development of therapeutic strategies to improve seizure control.

Localization and Registration of 2D Histological Mouse Brain Images in 3D Atlas Space.

To accurately explore the anatomical organization of neural circuits in the brain, it is crucial to map the experimental brain data onto a standardized system of coordinates. Studying 2D histological mouse brain slices remains the standard procedure in many laboratories. Mapping these 2D brain slices is challenging; due to deformations, artifacts, and tilted angles introduced during the standard preparation and slicing process. In addition, analysis of experimental mouse brain slices can be highly dependent on the level of expertise of the human operator. Here we propose a computational tool for Accurate Mouse Brain Image Analysis (AMBIA), to map 2D mouse brain slices on the 3D brain model with minimal human intervention. AMBIA has a modular design that comprises a localization module and a registration module. The localization module is a deep learning-based pipeline that localizes a single 2D slice in the 3D Allen Brain Atlas and generates a corresponding atlas plane. The registration module is built upon the Ardent python package that performs deformable 2D registration between the brain slice to its corresponding atlas. By comparing AMBIA's performance in localization and registration to human ratings, we demonstrate that it performs at a human expert level. AMBIA provides an intuitive and highly efficient way for accurate registration of experimental 2D mouse brain images to 3D digital mouse brain atlas. Our tool provides a graphical user interface and it is designed to be used by researchers with minimal programming knowledge.

Control of Theta Oscillatory Activity Underlying Fear Expression by mGlu5 Receptors.

Metabotropic glutamate 5 receptors (mGlu5) are thought to play an important role in mediating emotional information processing. In particular, negative allosteric modulators (NAMs) of mGlu5 have received a lot of attention as potential novel treatments for several neuropsychiatric diseases, including anxiety-related disorders. The aim of this study was to assess the influence of pre- and post-training mGlu5 inactivation in cued fear conditioned mice on neuronal oscillatory activity during fear retrieval. For this study we used the recently developed mGlu5 NAM Alloswicth-1 administered systemically. Injection of Alloswicth-1 before, but not after, fear conditioning resulted in a significant decrease in freezing upon fear retrieval. Mice injected with Alloswicth-1 pre-training were also implanted with recording microelectrodes into both the medial prefrontal cortex (mPFC) and ventral hippocampus (vHPC). The recordings revealed a reduction in theta rhythmic activity (4-12 Hz) in both the mPFC and vHPC during fear retrieval. These results indicate that inhibition of mGlu5 signaling alters local oscillatory activity in principal components of the fear brain network underlying a reduced response to a predicted threat.

VIP-expressing interneurons in the anterior insular cortex contribute to sensory processing to regulate adaptive behavior.

Adaptive behavior critically depends on the detection of behaviorally relevant stimuli. The anterior insular cortex (aIC) has long been proposed as a key player in the representation and integration of sensory stimuli, and implicated in a wide variety of cognitive and emotional functions. However, to date, little is known about the contribution of aIC interneurons to sensory processing. By using a combination of whole-brain connectivity tracing, imaging of neural calcium dynamics, and optogenetic modulation in freely moving mice across different experimental paradigms, such as fear conditioning and social preference, we describe here a role for aIC vasoactive intestinal polypeptide-expressing (VIP+) interneurons in mediating adaptive behaviors. Our findings enlighten the contribution of aIC VIP+ interneurons to sensory processing, showing that they are anatomically connected to a wide range of sensory-related brain areas and critically respond to behaviorally relevant stimuli independent of task and modality.

Loss of mGluR5 in D1 Receptor-Expressing Neurons Improves Stress Coping.

The metabotropic glutamate receptor type 5 (mGluR5) has been proposed to play a crucial role in the selection and regulation of cognitive, affective, and emotional behaviors. However, the mechanisms by which these receptors mediate these effects remain largely unexplored. Here, we studied the role of mGluR5 located in D1 receptor-expressing (D1) neurons in the manifestation of different behavioral expressions. Mice with conditional knockout (cKO) of mGluR5 in D1 neurons (mGluR5D1 cKO) and littermate controls displayed similar phenotypical profiles in relation to memory expression, anxiety, and social behaviors. However, mGluR5D1 cKO mice presented different coping mechanisms in response to acute escapable or inescapable stress. mGluR5D1 cKO mice adopted an enhanced active stress coping strategy upon exposure to escapable stress in the two-way active avoidance (TWA) task and a greater passive strategy upon exposure to inescapable stress in the forced swim test (FST). In summary, this work provides evidence for a functional integration of the dopaminergic and glutamatergic system to mediate control over internal states upon stress exposure and directly implicates D1 neurons and mGluR5 as crucial mediators of behavioral stress responses.

Inter-individual and inter-strain differences in cognitive and social abilities of Dark Agouti and Wistar Han rats.

Healthy animals displaying extreme behaviours that resemble human psychiatric symptoms are relevant models to study the natural psychobiological processes of maladapted behaviours. Using a Rat Gambling Task, healthy individuals spontaneously making poor decisions (PDMs) were found to co-express a combination of other cognitive and reward-based characteristics similar to symptoms observed in human patients with impulse-control disorders. The main goals of this study were to 1) confirm the existence of PDMs and their unique behavioural phenotypes in Dark Agouti (DA) and Wistar Han (WH) rats, 2) to extend the behavioural profile of the PDMs to probability-based decision-making and social behaviours and 3) to extract key discriminative traits between DA and WH strains, relevant for biomedical research. We have compared cognitive abilities, natural behaviours and physiological responses in DA and WH rats at the strain and at the individual level. Here we found that the naturally occurring PDM's profile was consistent between both rat lines. Then, although the PDM individuals did not take more risks in probability discounting task, they seemed to be of higher social ranks. Finally and despite their similarities in performance, WH and DA lines differed in degree of reward sensitivity, impulsivity, locomotor activity and open space-occupation. The reproducibility and conservation of the complex phenotypes of PDMs and GDMs (good decision makers) in these two genetically different strains support their translational potential. Both strains, present large phenotypic variation in behaviours pertinent for the study of the underlying mechanisms of poor decision making and associated disorders.

An Appraisal of the Influence of the Metabotropic Glutamate 5 (mGlu5) Receptor on Sociability and Anxiety.

Amongst the many neurotransmitter systems causally linked to the expression of social behavior, glutamate appears to play a pivotal role. In particular, metabotropic glutamate 5 (mGlu5) receptors have received much attention as its altered function has been reported in several mouse models of autism spectrum disorders and mental retardation. Inhibition of the activity of mGlu5 receptors by means of genetic or pharmacological manipulations improved social deficits in some of these animal models. However, in normal wild-type (WT) mice, pharmacological blockade of mGlu5 receptors yielded inconsistent results. The aim of our study was to investigate the actual contribution of decreased or absent mGlu5 receptor function in sociability and anxiety-like behavior as well as to explore the impact of mGlu5 receptor ablation on the pattern of brain activation upon social exposure. Here we show that Grm5-/- mice display higher social preference indexes compared to age-matched WT mice in the three-chambered social task. However, this effect was accompanied by a decreased exploratory activity during the test and increased anxiety-like behavior. Contrary to mGlu5 receptor ablation, the mGlu5 receptor negative allosteric modulator 3-((2-methyl-1,4-thiazolyl)ethynyl)pyridine (MTEP) induced anxiolytic effects without affecting social preference in WT mice. By mapping c-Fos expression in 21 different brain regions known to be involved in social interaction, we detected a specific activation of the prefrontal cortex and dorsolateral septum in Grm5-/- mice following social interaction. C-Fos expression correlation-based network and graph theoretical analyses further suggested dysfunctional connectivity and disruption of the functional brain network generated during social interaction in Grm5-/- mice. The lack of mGlu5 receptors resulted in profound rearrangements of the functional impact of prefrontal and hippocampal regions in the social interaction network. In conclusion, this work reveals a complex contribution of mGlu5 receptors in sociability and anxiety and points to the importance of these receptors in regulating brain functional connectivity during social interaction.

Controllability affects endocrine response of adolescent male rats to stress as well as impulsivity and behavioral flexibility during adulthood.

Exposure to stress during adolescence exerts a long-term impact on behavior and might contribute to the development of several neuropsychiatric disorders. In adults, control over stress has been found to protect from the negative consequences of stress, but the influence of controllability at early ages has not been extensively studied. Here, we evaluated in a rodent model the effects of repeated exposure in adolescent male rats to controllable versus uncontrollable foot-shock stress (CST or UST, respectively). Rats were assigned to three groups: non-stress (stress-naïve), CST (exposed to 8 sessions of a two-way shuttle active avoidance task over a period of 22 days) and UST (receiving the same amount of shocks as CST, regardless of their actual behavior). During adulthood, different cohorts were tested in several tasks evaluating inhibitory control and cognitive flexibility: 5-choice serial reaction time, delay-discounting, gambling test and probabilistic reversal learning. Results showed that the hypothalamic-pituitary-adrenal response to the first shock session was similar in CST and UST animals, but the response to the 8th session was lower in CST animals. In adulthood, the UST animals presented impaired motor (but not cognitive) impulsivity and more perseverative behavior. The behavioral effects of UST were associated with increased number of D2 dopamine receptors in dorsomedial striatum, but not in other striatal regions. In summary, UST exposure during adolescence induced long-term impairments in impulsivity and compulsivity, whereas CST had only minor effects. These data support a critical role of stress uncontrollability on the long-lasting consequences of stress, as a risk factor for mental illnesses.