Prefrontal 5α-reductase 2 mediates male-specific acute stress response.

A key response to acute stress is the increased brain synthesis of the neurosteroid allopregnanolone (AP). Although the rate-limiting step of this reaction is catalyzed by 5α-reductase (5αR), the role of its two primary isoenzymes, 5αR1 and 5αR2, in stress reactivity remains unclear. Here, we found that acute stress led to increased levels of 5αR2, but not 5αR1, in the medial prefrontal cortex (mPFC) of male, but not female, rats.

Exploring persistence in animal models: The sinking platform test.

Persistence is the capacity to sustain goal-oriented behavior despite recurring obstacles and setbacks. Recent studies have underscored the importance of this attribute as an integral facet of resilience and a protective factor against depression. In animal models, persistence is commonly examined through operant paradigms, wherein it is operationalized as resistance to the extinction of reward-directed actions.

Effect of 5-alpha reductase inhibitors in animal models of Parkinson's disease.

Parkinson's disease (PD) is characterized by motor symptoms due to loss of brain dopamine and non-motor symptoms, including gastrointestinal disorders. Although there is no cure for PD, symptomatic treatments are available. L-Dopa is the gold standard PD therapy, but most patients develop dyskinesias (LID), which are challenging to manage.

Colitis reduces active social engagement in mice and is ameliorated by supplementation with human microbiota members.

Multiple neurological disorders are associated with gastrointestinal (GI) symptoms, including autism spectrum disorder (ASD). However, it is unclear whether GI distress itself can modify aspects of behavior. Here, we show that mice that experience repeated colitis have impaired active social engagement, as measured by interactions with a foreign mouse, even though signs of colitis were no longer present.

The role of neuroactive steroids in tic disorders.

Tics are sudden, repetitive movements or vocalizations. Tic disorders, such as Tourette syndrome (TS), are contributed by the interplay of genetic risk factors and environmental variables, leading to abnormalities in the functioning of the cortico-striatal-thalamo-cortical (CSTC) circuitry. Various neurotransmitter systems, such as gamma-aminobutyric acid (GABA) and dopamine, are implicated in the pathophysiology of these disorders.

A novel naïve Bayes approach to identifying grooming behaviors in the force-plate actometric platform.

Background: Self-grooming behavior in rodents serves as a valuable behavioral index for investigating stereotyped and perseverative responses. Most current grooming analyses rely on video observation, which lacks standardization, efficiency, and quantitative information about force. To address these limitations, we developed an automated paradigm to analyze grooming using a force-plate actometer.

A novel naïve Bayes approach to identifying grooming behaviors in the force-plate actometric platform.

Background: Self-grooming behavior in rodents serves as a valuable model for investigating stereotyped and perseverative responses. Most current grooming analyses primarily rely on video observation, which lacks standardization, efficiency, and quantitative information about force. To address these limitations, we developed an automated paradigm to analyze grooming using a force-plate actometer.

A preliminary transcriptomic analysis of the orbitofrontal cortex of antisocial individuals.

Aims: Antisocial personality disorder (ASPD) and conduct disorder (CD) are characterized by a persistent pattern of violations of societal norms and others' rights. Ample evidence shows that the pathophysiology of these disorders is contributed by orbitofrontal cortex (OFC) alterations, yet the underlying molecular mechanisms remain elusive. To address this knowledge gap, we performed the first-ever RNA sequencing study of postmortem OFC samples from subjects with a lifetime diagnosis of ASPD and/or CD.

Prefrontal allopregnanolone mediates the adverse effects of acute stress in a mouse model of tic pathophysiology.

Ample evidence suggests that acute stress can worsen symptom severity in Tourette syndrome (TS); however, the neurobiological underpinnings of this phenomenon remain poorly understood. We previously showed that acute stress exacerbates tic-like and other TS-associated responses via the neurosteroid allopregnanolone (AP) in an animal model of repetitive behavioral pathology. To verify the relevance of this mechanism to tic pathophysiology, here we tested the effects of AP in a mouse model recapitulating the partial depletion of dorsolateral cholinergic interneurons (CINs) seen in post-mortem studies of TS.

Prefrontal allopregnanolone synergizes with D receptor activation to disrupt sensorimotor gating in male Sprague-Dawley rats.

Rationale: The prepulse inhibition (PPI) of the startle reflex is the best-established index of sensorimotor gating. We documented that the neurosteroid allopregnanolone (AP) is necessary to reduce PPI in response to D dopamine receptor agonists. Since Sprague-Dawley (SD) rats are poorly sensitive to the PPI-disrupting effects of these drugs, we hypothesized that AP might increase this susceptibility.

Acute stress impairs sensorimotor gating via the neurosteroid allopregnanolone in the prefrontal cortex.

Ample evidence indicates that environmental stress impairs information processing, yet the underlying mechanisms remain partially elusive. We showed that, in several rodent models of psychopathology, the neurosteroid allopregnanolone (AP) reduces the prepulse inhibition (PPI) of the startle, a well-validated index of sensorimotor gating. Since this GABA receptor activator is synthesized in response to acute stress, we hypothesized its participation in stress-induced PPI deficits.

Top2a promotes the development of social behavior via PRC2 and H3K27me3.

Little is understood about the embryonic development of sociality. We screened 1120 known drugs and found that embryonic inhibition of topoisomerase IIα (Top2a) resulted in lasting social deficits in zebrafish. In mice, prenatal Top2 inhibition caused defects in social interaction and communication, which are behaviors that relate to core symptoms of autism.

Relationship between adverse childhood experiences and symptom severity in adult men with Tourette Syndrome.

Childhood adversity is associated with the development or expression of many neuropsychiatric disorders, including those with strong genetic underpinnings. Despite reported associations between perceived stress and tic severity, the relationship between potentially traumatic events in childhood and Tourette Syndrome (TS), a highly heritable neuropsychiatric disorder, is unknown. This study aimed to assess whether exposure to eight categories of adverse childhood experiences (ACEs) is associated with TS severity and impairment, and whether TS genetic risk modifies this association.

Elevated levels of serotonin 5-HT receptors in the orbitofrontal cortex of antisocial individuals.

Antisocial behavior (ASB) is characterized by frequent violations of the rights and properties of others, as well as aggressive conduct. While ample evidence points to a critical role of serotonin in the emotional modulation of social responses, the implication of this neurotransmitter in ASB is unclear. Here, we performed the first-ever postmortem analysis of serotonergic markers in the orbitofrontal cortex (OFC) of male subjects with ASB (n = 9).

The mediating role of impulsivity in the associations between child maltreatment types and past month substance use.

Background: Child maltreatment has emerged as an important risk factor for substance use. However, despite evidence consistently demonstrating that substance use peaks during emerging adulthood, less is known about the specificity of maltreatment effects on substance use during this critical developmental period. Further, the factors that might play a role in these associations are not well understood.

Serotonin 5-HT receptor polymorphisms are associated with irritability and aggression in conduct disorder.

In childhood and adolescence, overt antisocial and aggressive manifestations are typically diagnosed as conduct disorder (CD). Given that the emerging research has pointed to the influence of 5-HT receptors in the ontogeny of aggression, we aimed to analyze the association of its genetic polymorphisms with CD. The study included 228 male adolescent subjects (120 with and 108 without CD).

Combined Antagonism of 5-HT and NMDA Receptors Reduces the Aggression of Monoamine Oxidase a Knockout Mice.

The enzyme monoamine oxidase A (MAOA) catalyzes the degradation of several neurotransmitters, including serotonin. A large body of evidence has shown that genetic MAOA deficiency predisposes humans and mice to aggression and antisocial behavior. We previously documented that the aggression of male MAOA-deficient mice is contributed by serotonin 5-HT and glutamate N-methyl-D-aspartate (NMDA) receptors in the prefrontal cortex (PFC).

Allopregnanolone: The missing link to explain the effects of stress on tic exacerbation?

The neurosteroid allopregnanolone (3α-hydroxy-5α-pregnan-20-one; AP) elicits pleiotropic effects in the central nervous system, ranging from neuroprotective and anti-inflammatory functions to the regulation of mood and emotional responses. Several lines of research show that the brain rapidly produces AP in response to acute stress to reduce the allostatic load and enhance coping. These effects not only are likely mediated by GABA receptor activation but also result from the contributions of other mechanisms, such as the stimulation of membrane progesterone receptors.