Excessive aggression induced by social isolation (SI) has been closely linked to dysfunction in prefrontal circuits, particularly the anterior cingulate cortex (ACC). Topiramate, an antiepileptic drug known to enhance GABAergic and inhibit glutamatergic transmission, has demonstrated antiaggressive effects. In our previous work, we showed that topiramate's antiaggressive effects were associated with reduced neuronal death, improved neuronal morphology, and attenuated neuroinflammation in the ACC following SI. However, its impact on ACC neuronal activity remains poorly understood. In this study, we investigated the effects of topiramate on the spontaneous activity of ACC neurons in a mouse model of SI-induced aggression. Additionally, we explored whether direct restoration of ACC activity via high-frequency stimulation could similarly reduce excessive aggression. Systemic administration of topiramate (30 mg/kg, intraperitoneally) significantly increased attack latency, reduced attack frequency, and enhanced sociability. In vivo extracellular recording of spontaneous activity revealed a 50% reduction in ACC firing in isolated mice, which was partially restored (∼30%) by topiramate treatment. Moreover, high-frequency stimulation applied to the ACC markedly decreased aggressive behavior and robustly promoted social interaction. Together, these results provide convergent behavioral and electrophysiological evidence that SI-induced aggression is associated with ACC hypoactivity. The finding that both topiramate treatment and high-frequency stimulation of the ACC effectively reversed these deficits highlights the ACC as a key target for therapeutic interventions to treat aggression-related neuropsychiatric conditions. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

Pathological aggression often results from the interaction between early-life adversity and later psychosocial stress. Maternal separation (MS) is an early-life stress model that increases vulnerability to aggression. However, social isolation (SI) is a paradigm for inducing aggressive behaviors and anterior cingulate cortex (ACC) alterations. Yet, the relationship between MS to adult behavior and ACC structure, and the modulatory role of SI during adolescence, remain unclear. This study examined the effects of MS, with or without SI, on aggression, anxiety, sensory sensitivity, and ACC morphology. Swiss albino pups underwent MS (4 h/day, PND2-20) and were later housed at PND46 for two weeks under standard or isolated conditions, which resulted four groups per sex: MS-/SI-, MS+/SI-, MS-/SI+, and MS+/SI+. Behavioral assessments were conducted in adulthood (PND60-62). The Resident-Intruder test indicated increased aggression exclusively in MS+/SI+ males, while social behavior declined in both sexes of MS+/SI- and MS+/SI+. The elevated plus maze showed increased anxiety specifically in MS+/SI+ females. Mechanical allodynia, assessed by the von Frey test, was observed in MS+/SI- and MS+/SI+ groups, with no changes in thermal sensitivity measured by the hot plate test. Morphological analyses using Nissl and Golgi-Cox staining revealed ACC alterations in MS+/SI- and MS+/SI+ mice of both sexes, including reduced neuronal density, shorter dendritic length, diminished branching, lower spine density, and decreased arborization complexity of pyramidal neurons. These results highlight a synergistic effect between MS and SI: MS predisposes individuals to SI's detrimental impact, while SI amplifies MS induced behavioral and neurobiological alterations. The ACC emerges as a critical substrate mediating the cumulative effects of stress on pathological aggression and its comorbidities.

Abstract The mediodorsal thalamus (MD) modulates pain through thalamocortical regulation of the mPFC. Yet, MD is often treated as a single anatomical and functional entity despite marked internal heterogeneity. Here, we tested whether medial-central MD (MDmc) and lateral MD (MDl) subdivisions exert dissociable control over sensory-discriminative and affective-motivational components of pain by engaging the anterior cingulate cortex (ACC) and prelimbic cortex (PrL). Using subdivision-selective excitotoxic lesions in rats, combined with anterograde tracing, laminar activity mapping, and projection-specific optogenetic manipulation of MDmc and MDl terminals in ACC or PrL, we determined the contribution of each subdivision and the underlying MD-PFC circuit mechanisms. Behaviorally, MDmc and MDl lesions induced mechanical and thermal hypersensitivity, but only MDmc lesions increased pain-related avoidance. Anatomical analyses showed that MDl preferentially innervated ACC PV cells, whereas MDmc more strongly targeted ACC SOM cells. Lesions further produced subdivision-dependent reorganization of nociception-evoked cFos activity in layers 2/3 and 5 and altered PV/SOM interneuron recruitment. Optogenetic manipulations revealed pathway-specific effects: MDmc-ACC/PrL manipulations enhanced nociceptive gain and avoidance, whereas MDl-ACC inhibition increased hypersensitivity while reducing avoidance, and MDl-PrL inhibition increased both nociceptive sensitivity and avoidance. Together, these findings identify MD subdivision-specific thalamocortical pathways that recruit distinct inhibitory microcircuits within ACC and PrL, thereby differentially shaping sensory-discriminative and affective-motivational components of pain.

Social isolation (SI) in rodents affects neuronal integrity and behavioral regulation. On the other hand, enriched environment (EE) has been reported to yield beneficial behavioral and neural effects in group-housed rodents. The midcingulate cortex (MCC) is a brain region that is increasingly implicated in socioemotional regulation; however, whether SI induces structural alterations in this region, and whether EE can mitigate such effects, remains unclear. In the present study, we examined the behavioral consequences of SI and the associated dendritic alterations in MCC pyramidal neurons. Furthermore, we evaluated the preventive potential of EE against SI-induced impairments. Adult male Swiss mice were housed for six weeks in grouped conditions, individually in standard conditions (SC isolated), or individually in an enriched environment (EE isolated) that contains sensory, motor, and cognitive stimuli. Behavioral assessments included aggression, sociability, and anxiety-like behavior. Subsequently, Golgi-Cox staining was used to quantify dendritic complexity and spine density in MCC pyramidal neurons. Our results showed that SI markedly increased aggression and anxiety-like behavior and reduced sociability. Importantly, it produced structural alterations in MCC, particularly reduced dendritic complexity and spine density, which point to this region as a structural target of SI. EE housing during SI attenuated behavioral alterations and preserved MCC dendritic structure, indicating a potential neuroprotective effect on neuronal morphology. These results provide new evidence that MCC is structurally vulnerable to SI and responsive to EE, which suggests that EE may be a valuable strategy to improve animal welfare and mitigate the impacts of prolonged SI.

Social anxiety disorder (SAD) stands as a prevalent psychiatric condition characterized by the apprehension of scrutiny and embarrassment in social settings, leading to anxiety symptoms, avoidance behaviors, and impaired social and occupational functioning. Despite the efficacy of various evidence-based treatments, a substantial portion of patients remain unresponsive. In this study, we used the socially enriched environment test (SEE, developed in our laboratory) to assess behaviors associated with social anxiety disorder after intervention, using various therapeutic strategies. We tested, in male mice, the effects of acute oxytocin injection, behavioral extinction, and high-frequency stimulation of the infralimbic (IL) cortex on social anxiety induced by a social fear conditioning paradigm. The SEE test revealed three behavioral changes, including reduced social interaction, reduced collective object exploration, and increased freezing behavior. Oxytocin and high-frequency stimulation of the IL cortex affected all these behavioral changes, while extinction training affected two (social interaction and freezing behavior). In conclusion, the SEE test is a reliable tool for exploring social anxiety behaviors in mice. Moreover, it can be used to evaluate different therapeutic approaches, providing valuable information on innovative therapeutic strategies for the effective treatment of SAD.

The mediodorsal thalamus plays a pivotal role in cognitive and emotional processes. Its heterogeneous subdivisions, medial, central, and lateral, exhibit distinct connectivity with prefrontal regions. However, their specific contributions to behavior and cortical inhibition remain unclear. NMDA-induced excitotoxic lesions in adult male and female Sprague-Dawley rats were made to selectively disrupt specific subdivisions of the MD (total MD, MDmc, and MDl). Subsequently, we evaluated changes in behavioral outcomes using the open field, elevated plus maze, social interaction, Y-maze, and passive avoidance tests. Alterations in GABAergic markers were also assessed by quantifying GAD67-expressing interneurons and GABAB receptor densities across cortical layers of the anterior cingulate cortex and prelimbic cortex using immunohistochemical procedures. MD lesions significantly impaired working memory, associative learning, and social behaviors. Specifically, MDl lesions induced significant hyperactivity, particularly in females. MDmc and total MD lesions increased anxiety-like behaviors, whereas MDl lesions decreased anxiety in males. Neurochemically, all MD lesions increased GAD67 expression and decreased GABAB receptor densities in layers 2/3 and 5 of the anterior cingulate cortex and the prelimbic cortex, with marked sex-dependent effects. These findings illustrate the functional specificity of MD subdivisions in modulating prefrontal circuits critical for behavior, providing novel insights into thalamocortical mechanisms and their relevance to neuropsychiatric disorders characterized by GABAergic dysfunction.

Glyphosate (Gly) is the active ingredient of several widely used herbicide formulations. Studies on Gly and glyphosate-based herbicide (GBH) exposure in different experimental models have suggested that the nervous system represented a key target for its toxicity, especially the prefrontal cortex (PFC). However, it is still unknown whether exposure to GBH affects higher brain functions dependent on PFC circuitry. The present work aimed to examine the effects of subtoxic doses of GBH on social cognition and cognitive flexibility as two functions belonging to higher brain function in mice. To do so, adult male mice were exposed daily to GBH by gavage at doses of 250 or 500 mg/kg for a sub-chronic period lasting 6 weeks. Then, mice were subjected to behavioral testing using the three-chamber and the Barnes maze paradigms. Our results indicate that GBH did not affect sociability. However, we found that GBH affects social cognition expressed by a lower discrimination index in the three-chamber test. Moreover, spatial memories evaluated during the probe trial, and cognitive flexibility evaluated during the reversal probe, were affected in mice exposed to GBH. Based on these results, exposure to subtoxic doses of GBH led to neurobehavioral alterations affecting the integrity of social cognition and cognitive flexibility functions. Finally, these data urge a thorough investigation of the cellular and molecular mechanisms underlying these alterations.

pathological pain and Attention-deficit/hyperactivity disorder (ADHD) are two complex multifactorial syndromes. The comorbidity of ADHD and altered pain perception is well documented in children, adolescents, and adults. According to pathophysiological investigations, the dopaminergic system's dysfunction provides a common basis for ADHD and comorbid pain. Growing evidence suggests that oxidative stress may be crucial in both pathologies. Recent studies revealed that a small peptide encompassing the redox-active site of selenoprotein T (PSELT), protects dopaminergic neurons and fibers as well as lesioned nerves in animal models. The current study aims to examine the effects of PSELT treatment on ADHD-like symptoms and pain sensitivity, as well as the role of catecholaminergic systems in these effects. Our results demonstrated that intranasal administration of PSELT reduced the hyperactivity in the open field, decreased the impulsivity displayed by 6-OHDA-lesioned male mice in the 5-choice serial reaction time task test and improved attentional performance. In addition, PSELT treatment significantly increased the nociception threshold in both normal and inflammatory conditions. Furthermore, anti-hyperalgesic activity was antagonized with sulpiride pre-treatment, but not by phentolamine, or propranolol pre-treatments. The present study suggests that PSELT reduces the severity of ADHD symptoms in mice and possesses potent antinociceptive effects which could be related to the involvement of D2/D3 dopaminergic receptors.

Metam sodium-based pesticide (MS-BP) is widely used in agriculture and public health. We have previously demonstrated that maternal exposure to MS-BP resulted in sensorimotor alterations in mice offspring with long-lasting deficits including anxiety- and depression-like behaviors. Here, we project to verify whether these two neurobehavioral effects occur during adulthood following direct exposure to MS-BP and whether it results in changes in the serotoninergic system and gut microbiota. Our findings showed that chronic exposure to MS-BP increased anxiety- and depression-like behaviors, accompanied by a depletion of serotonin-like neurons within the dorsal raphe nucleus and a reduction in serotoninergic terminals in the infralimbic cortex and the basolateral amygdala. In addition, all MS-BP-exposed animals exhibited a reduced total bacterial number and diversity of gut microbiota. Taken together, our data demonstrated that MS-BP-induced behavioral changes could be related to the impairment of the serotoninergic system and gut microbiota dysbiosis.

Cognitive integrity is a critical aspect of neurological function, and a decline in cognitive function is a hallmark of neurotoxicity. Oxidative stress is a significant pathological feature contributing to cognitive deficits that can arise from exposure to environmental pollutants such as pesticides. Among these, Metam sodium-based pesticides (MS-BP) are an emergent type of pesticide widely used in the agriculture and public health sectors for controlling pests and diseases. Our prior research has shown that animals exposed to MS-BP during the early stages of brain development caused cognitive impairments. In the present study, we tested whether exposure to this compound in a fully matured brain would affect cognitive performance and induce oxidative damage to the central nervous system. In this context, adult mice received chronic treatment with increasing doses of MS-BP and subjected to a set of behavioral paradigms. Following behavioral assessment, oxidative stress and glial activation were evaluated. Our main findings showed that MS-BP chronic exposure impaired recognition and short- and long-term memory. These alterations were accompanied by increased superoxide dismutase activity and malondialdehyde level and a marked decrease in catalase activity in specific brain areas. Moreover, exposure to MS-BP is associated with a significant rise in the density of astrocytic and microglial markers, indicating a possible glial cell response within the prefrontal cortex and hippocampus. The present work demonstrated that MS-BP altered cognitive performance likely through oxidative damage to the brain.