Compulsive Social Behavior Emerges after Selective Ablation of Striatal Cholinergic Interneurons.

The mechanisms underlying social dysfunction in neuropsychiatric conditions such as obsessive-compulsive disorder and Tourette syndrome remain uncertain. However, it is known that dysfunctions in basal ganglia, including a reduced number of striatal cholinergic interneurons (SCIN), are involved in their pathophysiology. To explore the role of SCIN in relation to perseverative behaviors, we characterized a new transgenic mouse model in which inducible ablation of SCIN is achieved with high efficiency in a cell-type- and region-specific manner. Mice were subjected to extensive behavioral testing, including assessment of social behaviors, and corticostriatal functional connectivity was evaluated in vivo Selective SCIN ablation leads to altered social interactions together with exacerbated spontaneously emitted repetitive behaviors. Lesioned mice showed normal motor coordination, balance, and general locomotion. Interestingly, only environmentally driven, but not self-directed, repetitive behaviors were exacerbated in lesioned mice. Remarkably, in mice with SCIN ablation, the normal pattern of social exploration was replayed continuously. The emerging pattern of social interactions is highly predictable and invariant across time. In vivo electrophysiological recordings indicate that SCIN ablation results in an increase of the functional connectivity between different cortical areas and the motor, but not associative, region of the striatum. Our results identify a role of SCIN in suppressing perseverative behaviors, including socially related ones. In sum, SCIN ablation in mice leads to exacerbated ritualistic-like behaviors that affect social performance, providing a link between SCIN dysfunction and the social impairments present in psychiatric disorders.SIGNIFICANCE STATEMENT We sought to uncover the impact of striatal cholinergic interneuron (SCIN) degeneration on perseverative behaviors related to obsessive-compulsive disorder (OCD) and Tourette syndrome (TS). We found that extensive SCIN ablation results in exacerbated social interactions, in which normal social contacts were replayed continuously in a highly stereotyped, ritualistic pattern. SCIN ablation also leads to an increase in other spontaneously emitted repetitive behaviors without alteration of motor coordination, balance, or locomotion. Moreover, we identify an increase of functional connectivity between frontal cortical areas and the motor region of the striatum as a putative substrate for the observed behavioral alterations. Therefore, perseveration induced by SCIN ablation extends to social performance as occurs in neuropsychiatric conditions such as OCD and TS.

Schizophrenia and reelin: a model based on prenatal stress to study epigenetics, brain development and behavior.

Schizophrenia is a severe psychiatric disorder that results in a significant disability for the patient. The disorder is characterized by impairment of the adaptive orchestration of actions, a cognitive function that is mainly dependent on the prefrontal cortex. This behavioral deficit, together with cellular and neurophysiological alterations in the prefrontal cortex, as well as reduced density of GABAergic cells and aberrant oscillatory activity, all indicate structural and functional deficits of the prefrontal cortex in schizophrenia. Among the several risk factors for the development of schizophrenia, stress during the prenatal period has been identified as crucial. Thus, it is proposed that prenatal stress induces neurodevelopmental alterations in the prefrontal cortex that are expressed as cognitive impairment observed in schizophrenia. However, the precise mechanisms that link prenatal stress with the impairment of prefrontal cortex function is largely unknown. Reelin is an extracellular matrix protein involved in the development of cortical neural connectivity at embryonic stages, and in synaptic plasticity at postnatal stages. Interestingly, down-regulation of reelin expression has been associated with epigenetic changes in the reelin gene of the prefrontal cortex of schizophrenic patients. We recently showed that, similar to schizophrenic patients, prenatal stress induces down-expression of reelin associated with the methylation of its promoter in the rodent prefrontal cortex. These alterations were paralleled with altered prefrontal cortex functional connectivity and impairment in prefrontal cortex-dependent behavioral tasks. Therefore, considering molecular, cellular, physiological and behavioral evidence, we propose a unifying framework that links prenatal stress and prefrontal malfunction through epigenetic alterations of the reelin gene.

Schizophrenia and reelin: a model based on prenatal stress to study epigenetics, brain development and behavior

Schizophrenia is a severe psychiatric disorder that results in a significant disability for the patient. The disorder is characterized by impairment of the adaptive orchestration of actions, a cognitive function that is mainly dependent on the prefrontal cortex. This behavioral deficit, together with cellular and neurophysiological alterations in the prefrontal cortex, as well as reduced density of GABAergic cells and aberrant oscillatory activity, all indicate structural and functional deficits of the prefrontal cortex in schizophrenia. Among the several risk factors for the development of schizophrenia, stress during the prenatal period has been identified as crucial. Thus, it is proposed that prenatal stress induces neurodevelopmental alterations in the prefrontal cortex that are expressed as cognitive impairment observed in schizophrenia. However, the precise mechanisms that link prenatal stress with the impairment of prefrontal cortex function is largely unknown. Reelin is an extracellular matrix protein involved in the development of cortical neural connectivity at embryonic stages, and in synaptic plasticity at postnatal stages. Interestingly, down-regulation of reelin expression has been associated with epigenetic changes in the reelin gene of the prefrontal cortex of schizophrenic patients. We recently showed that, similar to schizophrenic patients, prenatal stress induces down-expression of reelin associated with the methylation of its promoter in the rodent prefrontal cortex. These alterations were paralleled with altered prefrontal cortex functional connectivity and impairment in prefrontal cortex-dependent behavioral tasks. Therefore, considering molecular, cellular, physiological and behavioral evidence, we propose a unifying framework that links prenatal stress and prefrontal malfunction through epigenetic alterations of the reelin gene.

[Autism spectrum disorder and specific language disorder. Are two different entities or a continuum of neuropsychological manifestations?]. / Trastorno del espectro autista y trastorno específico del lenguaje ¿Dos entidades diferentes o un continuo de manifestaciones neuropsicológicas?

Follow-up of children with delayed language development underscores the fact that, in several cases, language difficulties coexist with other symptoms such as social behavior changes. Autism spectrum disorder (ASD) and language specific disorder (LSD) are developmental disorders that are defined differently, but have some common language and social behavior characteristics which impose diagnostic difficulties. For this reason it is believed that they may share not only symptomatic but also ethiological aspects. With that in mind, we performed a literature search of works that discussed and, with their results, clarified this issue. Although several studies have allowed clearer and frequent diagnosis of both ASD and LSD, many cases persist in which the question in this article's title cannot be clearly answered, especially in children younger than two years of age.

Contextual social cognition impairments in schizophrenia and bipolar disorder.

BACKGROUND: The ability to integrate contextual information with social cues to generate social meaning is a key aspect of social cognition. It is widely accepted that patients with schizophrenia and bipolar disorders have deficits in social cognition; however, previous studies on these disorders did not use tasks that replicate everyday situations. METHODOLOGY/PRINCIPAL FINDINGS: This study evaluates the performance of patients with schizophrenia and bipolar disorders on social cognition tasks (emotional processing, empathy, and social norms knowledge) that incorporate different levels of contextual dependence and involvement of real-life scenarios. Furthermore, we explored the association between social cognition measures, clinical symptoms and executive functions. Using a logistic regression analysis, we explored whether the involvement of more basic skills in emotional processing predicted performance on empathy tasks. The results showed that both patient groups exhibited deficits in social cognition tasks with greater context sensitivity and involvement of real-life scenarios. These deficits were more severe in schizophrenic than in bipolar patients. Patients did not differ from controls in tasks involving explicit knowledge. Moreover, schizophrenic patients' depression levels were negatively correlated with performance on empathy tasks. CONCLUSIONS/SIGNIFICANCE: Overall performance on emotion recognition predicted performance on intentionality attribution during the more ambiguous situations of the empathy task. These results suggest that social cognition deficits could be related to a general impairment in the capacity to implicitly integrate contextual cues. Important implications for the assessment and treatment of individuals with schizophrenia and bipolar disorders, as well as for neurocognitive models of these pathologies are discussed.

Trastorno del espectro autista y trastorno específico del lenguaje ¿Dos entidades diferentes o un continuo de manifestaciones neuropsicológicas? / [Autism spectrum disorder and specific language disorder. Are two different entities or a continuum of neuropsychological manifestations?].

Follow-up of children with delayed language development underscores the fact that, in several cases, language difficulties coexist with other symptoms such as social behavior changes. Autism spectrum disorder (ASD) and language specific disorder (LSD) are developmental disorders that are defined differently, but have some common language and social behavior characteristics which impose diagnostic difficulties. For this reason it is believed that they may share not only symptomatic but also ethiological aspects. With that in mind, we performed a literature search of works that discussed and, with their results, clarified this issue. Although several studies have allowed clearer and frequent diagnosis of both ASD and LSD, many cases persist in which the question in this articles title cannot be clearly answered, especially in children younger than two years of age.

Trastorno del espectro autista y trastorno específico del lenguaje ¿Dos entidades diferentes o un continuo de manifestaciones neuropsicológicas? / [Autism spectrum disorder and specific language disorder. Are two different entities or a continuum of neuropsychological manifestations?].

Follow-up of children with delayed language development underscores the fact that, in several cases, language difficulties coexist with other symptoms such as social behavior changes. Autism spectrum disorder (ASD) and language specific disorder (LSD) are developmental disorders that are defined differently, but have some common language and social behavior characteristics which impose diagnostic difficulties. For this reason it is believed that they may share not only symptomatic but also ethiological aspects. With that in mind, we performed a literature search of works that discussed and, with their results, clarified this issue. Although several studies have allowed clearer and frequent diagnosis of both ASD and LSD, many cases persist in which the question in this article’s title cannot be clearly answered, especially in children younger than two years of age.

Contextual social cognition and the behavioral variant of frontotemporal dementia.

The significance of social situations is commonly context-embedded. Although the role of context has been extensively studied in basic sensory processing or simple stimulus-response settings, its relevance for social cognition is unknown. We propose the social context network model (SCNM), a fronto-insular-temporal network responsible for processing social contextual effects. The SCNM may 1) update the context and use it to make predictions, 2) coordinate internal and external milieus, and 3) consolidate context-target associative learning. We suggest the behavioral variant of frontotemporal dementia (bvFTD) as a specific disorder in which the reported deficits in social cognition (e.g., facial recognition, empathy, decision-making, figurative language, theory of mind) can be described as context impairments due to deficits in the SCNM. Disruption of orbitofrontal-amygdala circuit, as well as the frontal, temporal, and insular atrophy in bVFTD, suggests a relationship between context-sensitive social cognition and SCNM. In considering context as an intrinsic part of social cognition, we highlight the need for a situated cognition approach in social cognition research as opposed to an abstract, universal, and decontextualized approach. The assessment of context-dependent social cognition paradigms, the SCNM, and their possible application to neuropsychiatric disorders may provide new insight into bvFTD and other related frontal disorders.

Evaluation of bilateral cingulotomy and anterior capsulotomy for the treatment of aggressive behavior.

BACKGROUND: Agressiveness is a psychiatric symptom that may be part of schizophrenia, mental retardation, drug abuse and other conditions. Surgical treatment remains controversial and few therapeutic options are available. We undertook this study to perform a prospective analysis on the efficacy and safety of bilateral cingulotomy and anterior capsulotomy in the treatment of aggressiveness behavior. METHODS: We studied 25 patients with a primary diagnosis of aggressiveness refractory to conventional treatment. Subjects were clinically evaluated with the Mayo-Portland adaptability inventory and the Global Assessment of Functioning score. Lesions were placed stereotactically in both targets and confirmed by postoperative magnetic resonance imaging. Significant changes were evaluated with Wilcoxon test after 3 and 6 months. RESULTS: According to inclusion and exclusion criteria, only 12 patients were finally included and surgical treated. Lesions significantly decreased using the Mayo-Portland adaptability inventory and the Global Assessment of Functioning score (p <0.002) at 3 and 6 months follow-up. Only five patients showed either mild or transitory postsurgical complications. CONCLUSIONS: Combined bilateral anterior capsulotomy and cingulotomy successfully reduced aggressiveness behavior and improved clinical evaluations. These effects were obtained with fewer complications than previously described targets.

The interface of oxytocin-labeled cells and serotonin transporter-containing fibers in the primate hypothalamus: a substrate for SSRIs therapeutic effects?

Oxytocin (OT) is a neuropeptide synthesized in the paraventricular (PVN) and supraoptic nuclei (SON) in the hypothalamus. Although OT is more commonly known for its role in the milk-ejection reflex, in recent years research has indicated that OT participates in the expression of social behavior, memory processing, modulation of fear, and stress responses. The demonstration that OT influences affiliative behaviors, such as parental care and reproduction, and decreases anxiety has lead to speculations that it may have a role in mood disorders. Evidence from pharmacologic studies, pointing out the modulation of the OT system by serotonin, has argued in favor of OT as a mediator of serotonin reuptake inhibitors (SSRIs) antidepressant properties. In the present study, we investigated the distribution and overlap of OT-labeled cells and serotonin transporter (5-HTT) immunoreactive (IR) fibers in the Macaque hypothalamus, utilizing immunocytochemical and double-immunofluorescent techniques. Consistent with previous reports, the distribution of OT-labeled cells in the hypothalamus is confined to the PVN and SON. In these nuclei, we demonstrate that the distribution of 5-HTT-labeled fibers follows the distribution of OT-labeled cells. Overlap of OT-labeled neurons and 5-HTT-IR fibers occurs in the parvicellular, magnocellular, dorsal, and posterior subdivisions of the PVN. In the SON, 5-HTT-labeled fibers and OT-labeled cells overlap in the ventromedial subdivision and in the 'capsular' part of the dorsolateral SON. These findings provide neuroanatomic support for the idea that SSRIs' therapeutic effects on social affiliation and anxiety may be mediated in part through components of the OT system.

Impairments of social behavior and memory after neonatal gastrin-releasing peptide receptor blockade in rats: Implications for an animal model of neurodevelopmental disorders.

The gastrin-releasing peptide receptor (GRPR) has been implicated in central nervous system (CNS) diseases, including neurodevelopmental disorders associated with autism. In the present study we examined the effects of GRPR blockade during the neonatal period on behavioral measures relevant to animal models of neurodevelopmental disorders. Male Wistar rats were given an intraperitoneal (i.p.) injection of either saline (SAL) or the GRPR antagonist [D-Tpi(6), Leu(13) psi(CH(2)NH)-Leu(14)] bombesin (6-14) (RC-3095; 1 or 10mg/kg) twice daily for 10days from postnatal days (PN) 1 to 10. Animals treated with RC-3095 showed pronounced deficits in social interaction when tested at PN 30-35 and impaired 24-h retention of memory for both novel object recognition (NOR) and inhibitory avoidance (IA) tasks tested at PN 60-71. Neither short-term memory tested 1.5h posttraining nor open field behavior were affected by neonatal GRPR blockade. The implications of the findings for animal models of neurodevelopmental disorders are discussed.