Background: The social motivational theory of autism spectrum disorder (ASD) focuses on social anhedonia as key causal feature of the impaired peer relationships that characterize ASD patients. ASD prevalence is higher in boys, but increasing evidence suggests underdiagnosis and undertreatment in girls. We showed that stress-induced motivational anhedonia is relieved by repeated treatment with fenofibrate (FBR), a peroxisome proliferator-activated receptor α (PPARα) agonist. Here, we used the valproic acid (VPA) model of ASD in rats to examine male and female phenotypes and assess whether FBR administration from weaning to young adulthood relieved social impairments. Methods: Male and female rats exposed to saline or VPA at gestational day 12.5 received standard or FBR-enriched diet from postnatal day 21 to 48–53, when behavioral tests and ex vivo neurochemical analyses were performed. Phosphorylation levels of DARPP-32 in response to social and nonsocial cues, as index of dopamine D₁ receptor activation, levels of expression of PPARα, vesicular glutamatergic and GABAergic transporters, and postsynaptic density protein PSD-95 were analyzed by immunoblotting in selected brain regions. Results: FBR administration relieved social impairment and perseverative behavior in VPA-exposed male and female rats, but it was only effective on female stereotypies. Dopamine D₁ receptor signaling triggered by social interaction in the nucleus accumbens shell was blunted in VPA-exposed rats, and it was rescued by FBR treatment only in males. VPA-exposed rats of both sexes exhibited an increased ratio of striatal excitatory over inhibitory synaptic markers that was normalized by FBR treatment. Limitations: This study did not directly address the extent of motivational deficit in VPA-exposed rats and whether FBR administration restored the likely decreased motivation to operate for social reward. Future studies using operant behavior protocols will address this relevant issue. Conclusions: The results support the involvement of impaired motivational mechanisms in ASD-like social deficits and suggest the rationale for a possible pharmacological treatment. Moreover, the study highlights sex-related differences in the expression of ASD-like symptoms and their differential responses to FBR treatment.

Peroxisome proliferator-activator receptors (PPARs) regulate lipid and glucose metabolism, control inflammatory processes, and modulate several brain functions. Three PPAR isoforms have been identified, PPARα, PPARβ/δ, and PPARγ, which are expressed in different tissues and cell types. Hereinafter, we focus on PPARα involvement in the pathophysiology of neuropsychiatric and neurodegenerative disorders, which is underscored by PPARα localization in neuronal circuits involved in emotion modulation and stress response, and its role in neurodevelopment and neuroinflammation. A multiplicity of downstream pathways modulated by PPARα activation, including glutamatergic neurotransmission, upregulation of brain-derived neurotrophic factor, and neurosteroidogenic effects, encompass mechanisms underlying behavioral regulation. Modulation of dopamine neuronal firing in the ventral tegmental area likely contributes to PPARα effects in depression, anhedonia, and autism spectrum disorder (ASD). Based on robust preclinical evidence and the initial results of clinical studies, future clinical trials should assess the efficacy of PPARα agonists in the treatment of mood and neurodevelopmental disorders, such as depression, schizophrenia, and ASD.

Growing preclinical and clinical evidence highlights neurosteroid pathway imbalances in Parkinson's Disease (PD) and L-DOPA-induced dyskinesias (LIDs). We recently reported that 5α-reductase (5AR) inhibitors dampen dyskinesias in parkinsonian rats; however, unraveling which specific neurosteroid mediates this effect is critical to optimize a targeted therapy. Among the 5AR-related neurosteroids, striatal pregnenolone has been shown to be increased in response to 5AR blockade and decreased after 6-OHDA lesions in the rat PD model. Moreover, this neurosteroid rescued psychotic-like phenotypes by exerting marked antidopaminergic activity. In light of this evidence, we investigated whether pregnenolone might dampen the appearance of LIDs in parkinsonian drug-naïve rats. We tested 3 escalating doses of pregnenolone (6, 18, 36 mg/kg) in 6-OHDA-lesioned male rats and compared the behavioral, neurochemical, and molecular outcomes with those induced by the 5AR inhibitor dutasteride, as positive control. The results showed that pregnenolone dose-dependently countered LIDs without affecting L-DOPA-induced motor improvements. Post-mortem analyses revealed that pregnenolone significantly prevented the increase of validated striatal markers of dyskinesias, such as phospho-Thr-34 DARPP-32 and phospho-ERK_1/2, as well as D₁-D₃ receptor co-immunoprecipitation in a fashion similar to dutasteride. Moreover, the antidyskinetic effect of pregnenolone was paralleled by reduced striatal levels of BDNF, a well-established factor associated with the development of LIDs. In support of a direct pregnenolone effect, LC/MS-MS analyses revealed that striatal pregnenolone levels strikingly increased after the exogenous administration, with no significant alterations in downstream metabolites. All these data suggest pregnenolone as a key player in the antidyskinetic properties of 5AR inhibitors and highlight this neurosteroid as an interesting novel tool to target LIDs in PD.

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. Down-regulation of 5αR2 in the mPFC significantly reduced stress response in males, and similar sexual dimorphic effects were observed in a novel line of 5αR2 knockout rats. Notably, 5αR1 regulated baseline AP synthesis, whereas 5αR2 enabled AP production under stress. Acute AP administration restored stress response in 5αR2 knockdown rats. Single-nucleus transcriptomics showed that 5αR2 enabled stress-induced protein translation in neurons and glia. These results highlight the crucial role of 5αR2 in mediating sex-specific differences in acute stress reactivity.

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.Methods: The transcriptomic profiles of OFC samples from subjects with ASPD and/or CD were compared to those of unaffected age‐matched controls (n = 9/group).Results: The OFC of ASPD/CD‐affected subjects displayed significant differences in the expression of 328 genes. Further gene‐ontology analyses revealed an extensive downregulation of excitatory neuron transcripts and upregulation of astrocyte transcripts. These alterations were paralleled by significant modifications in synaptic regulation and glutamatergic neurotransmission pathways.Conclusion: These preliminary findings suggest that ASPD and CD feature a complex array of functional deficits in the pyramidal neurons and astrocytes of the OFC. In turn, these aberrances may contribute to the reduced OFC connectivity observed in antisocial subjects. Future analyses on larger cohorts are needed to validate these results.