Ceftriaxone alters the gut microbiome composition and reduces alcohol intake in male and female Sprague-Dawley rats.

Ceftriaxone is an antibiotic that increases central nervous system (CNS) protein expression of the glutamate transporters GLT-1 and xCT and ameliorates pathological behaviors in rodent models of neurological disease and substance use disorder. However, little ceftriaxone passes through the blood-brain barrier, the CNS binding partner of ceftriaxone is unknown, and ceftriaxone does not consistently upregulate GLT-1 and xCT in cell culture. Ceftriaxone alters the gut microbiome composition in rodents and humans, and the microbiome-gut-brain axis regulates drug-seeking. Thus, here we test the hypothesis that ceftriaxone reduces alcohol intake while ameliorating alcohol-induced disruption of the gut microbiome composition. Male and female Sprague-Dawley rats received intermittent access to alcohol (IAA) while controls received access to only water. Following 17 IAA sessions, ceftriaxone/vehicle treatment was given for 5 days. Analysis of the gut microbiome composition was assessed by 16S rRNA gene amplicon sequencing conducted on fecal pellets collected prior to and after alcohol consumption and following ceftriaxone treatment. Male rats displayed escalated alcohol intake and preference over the course of the 17 sessions; however, total alcohol intake did not differ between the sexes. Ceftriaxone reduced alcohol intake and preference in male and female rats. While alcohol affected a diverse set of amplicon sequencing variants (ASV), ceftriaxone markedly reduced the diversity of microbial communities reflected by a blooming of the Enterococcaceae family. The remaining effects of ceftriaxone, however, encompassed families both affected and unaffected by prior alcohol drinking and highlight the Ruminococcaceae and Muribaculaceae families as bidirectionally modulated by alcohol and ceftriaxone. Altogether, our study confirms that ceftriaxone reduces alcohol intake in rats and partially reverses alcohol-induced dysbiosis.

Transcriptomic analysis of paternal behaviors in prairie voles.

BACKGROUND: The importance of fathers' engagement in care and its critical role in the offspring's cognitive and emotional development is now well established. Yet, little is known on the underlying neurobiology due to the lack of appropriate animal models. In the socially monogamous and bi-parental prairie vole (Microtus ochrogaster), while 60-80% of virgin males show spontaneous paternal behaviors (Paternal), others display pup-directed aggression (Attackers). Here we took advantage of this phenotypic dichotomy and used RNA-sequencing in three important brain areas to characterize gene expression associated with paternal behaviors of Paternal males and compare it to experienced Fathers and Mothers. RESULTS: While Paternal males displayed the same range and extent of paternal behaviors as experienced Fathers, we observed structure-specific transcriptomic differences between parental behaviors phenotypes. Using differential expression, gene set expression, as well as co-expression network analyses, we found that phenotypic differences between Paternal males and Attackers were mainly reflected by the lateral septum (LS), and to a lower extent, the nucleus accumbens (NAc), transcriptomes. In the medial preoptic area (MPOA), the profiles of gene expression mainly reflected differences between females and males regardless of their parental behaviors phenotype. Functional enrichment analyses of those gene sets associated with Paternal males or Attackers in the LS and the NAc revealed the involvement of processes related to the mitochondria, RNA translation, protein degradation processes, as well as epigenetic regulation of gene expression. CONCLUSIONS: By leveraging the natural phenotypic differences in parental behaviors in virgin male prairie voles alongside fathers and mothers, we identified a marked structure- and phenotype-specific pattern of gene expression associated with spontaneous paternal behaviors independently from fatherhood and pair-bonding. The LS transcriptome related to the mitochondria, RNA translation, and protein degradation processes was thus highlighted as a primary candidate associated with the spontaneous display of paternal behaviors. Altogether, our observations further characterize the behavioral and transcriptomic signature of parental behaviors in the socially monogamous prairie vole and lay the groundwork to further our understanding of the molecular underpinnings of paternal behavior.

Epigenetics of Aggression.

Aggression is a complex behavioral trait modulated by both genetic and environmental influences on gene expression. By controlling gene expression in a reversible yet potentially lasting manner in response to environmental stimulation, epigenetic mechanisms represent prime candidates in explaining both individual differences in aggression and the development of elevated aggressive behaviors following life adversity. In this manuscript, we review the evidence for an epigenetic basis in the development and expression of aggression in both humans and related preclinical animal models. In particular, we discuss reports linking DNA methylation, histone post-translational modifications, as well as non-coding RNA, to the regulation of a variety of genes implicated in the neurobiology of aggression including neuropeptides, the serotoninergic and dopaminergic systems, and stress response related systems. While clinical reports do reveal interesting patterns of DNA methylation underlying individual differences and experience-induced aggressive behaviors, they do, in general, face the challenge of linking peripheral observations to central nervous system regulations. Preclinical studies, on the other hand, provide detailed mechanistic insights into the epigenetic reprogramming of gene expression following life adversities. Although the functional link to aggression remains unclear in most, these studies together do highlight the involvement of epigenetic events driven by DNA methylation, histone modifications, and non-coding RNA in the neuroadaptations underlying the development and expression of aggression.

Transcriptomic Regulations Underlying Pair-bond Formation and Maintenance in the Socially Monogamous Male and Female Prairie Vole.

BACKGROUND: The ability to form enduring social bonds is characteristic of human nature, and impairments in social affiliation are central features of severe neuropsychiatric disorders including autism spectrum disorder and schizophrenia. Owing to its ability to form long-term pair-bonds, the socially monogamous prairie vole has emerged as an excellent model to study the neurobiology of social attachment. Despite the enduring nature of the bond, however, surprisingly few genes have been implicated in the pair-bonding process in either sex. METHODS: Male and female prairie voles (Microtus ochrogaster) were cohabitated with an opposite-sex partner for 24 hours or 3 weeks, and transcriptomic regulations in the nucleus accumbens were measured by RNA sequencing. RESULTS: We found sex-specific response patterns despite similar behavioral indicators of pair-bond establishment. Indeed, 24 hours of cohabitation with an opposite-sex partner induced widespread transcriptomic changes that remained sustained to some extent in females after 3 weeks but returned to baseline before a second set of regulations in males. This led to a highly sexually biased nucleus accumbens transcriptome at 3 weeks related to processes such as neurotransmission, protein turnover, and DNA transcription. In particular, we found sex-specific alterations of mitochondrial dynamics following cohabitation, with a shift toward fission in males. CONCLUSIONS: In addition to identifying the genes, networks, and pathways involved in the pair-bonding process in the nucleus accumbens, our work illustrates the vast extent of sex differences in the molecular mechanisms underlying pair-bonding in prairie voles and paves the way to further our understanding of the complex social bonding process.

Epigenetic regulation of motivated behaviors by histone deacetylase inhibitors.

Growing evidence has begun to elucidate the contribution of epigenetic mechanisms in the modulation and maintenance of gene expression and behavior. Histone acetylation is one such epigenetic mechanism, which has been shown to profoundly alter gene expression and behaviors. In this review, we begin with an overview of the major epigenetic mechanisms including histones acetylation. We next focus on recent evidence about the influence of environmental stimuli on various motivated behaviors through histone acetylation and highlight how histone deacetylase inhibitors can correct some of the pathologies linked to motivated behaviors including substance abuse, feeding and social attachments. Particularly, we emphasize that the effects of histone deacetylase inhibitors on motivated behaviors are time and context-dependent.

Hippocampal protein kinase D1 is necessary for DHPG-induced learning and memory impairments in rats.

BACKGROUND: Understanding molecular mechanisms underlying the induction of learning and memory impairments remains a challenge. Recent investigations have shown that the activation of group I mGluRs (mGluR1 and mGluR5) in cultured hippocampal neurons by application of (S)-3,5-Dihydroxyphenylglycine (DHPG) causes the regulated internalization of N-methyl-D-aspartate receptors (NMDARs), which subsequently activates protein kinase D1 (PKD1). Through phosphorylating the C-terminals of the NMDAR GluN2 subunits, PKD1 down-regulates the activity of remaining (non-internalized) surface NMDARs. The knockdown of PKD1 does not affect the DHPG-induced inhibition of AMPA receptor-mediated miniature excitatory post-synaptic currents (mEPSCs) but prevents the DHPG-induced inhibition of NMDAR-mediated mEPSCs in vitro. Thus, we investigated the in vivo effects of bilateral infusions of DHPG into the hippocampal CA1 area of rats in the Morris water maze (MWM) and the novel object discrimination (NOD) tests. METHODS: A total of 300 adult male Sprague Dawley rats (250-280 g) were used for behavioral tests. One hundred ninety four were used in MWM test and the other 106 rats in the NOD test. Following one week of habituation to the vivarium, rats were bilaterally implanted under deep anesthesia with cannulas aimed at the CA1 area of the hippocampus (CA1 coordinates in mm from Bregma: AP -3.14; lateral +/-2; DV -3.0). Through implanted cannulas artificial cerebrospinal fluid (ACSF), the group1 mGluR antagonist 6-Methyl-2-(phenylethynyl)pyridine (MPEP), the dynamin-dependent internalization inhibitor Dynasore, or the PKD1 inhibitor CID755673 were infused into the bilateral hippocampal CA1 areas (2 µL per side, over 5 min). The effects of these infusions and the effects of PKD1 knockdown were examined in MWM or NOD test. RESULTS: DHPG infusion increased the latency to reach the platform in the MWM test and reduced the preference for the novel object in the NOD task. We found that the DHPG effects were dose-dependent and could be maintained for up to 2 days. Notably, these effects could be prevented by pre-infusion of the group1 mGluR antagonist MPEP, the dynamin-dependent internalization inhibitor Dynasore, the PKD1 inhibitor CID755673, or by PKD1 knockdown in the hippocampal CA1 area. CONCLUSION: Altogether, these findings provide direct evidence that PKD1-mediated signaling may play a critical role in the induction of learning and memory impairments by DHPG infusion into the hippocampal CA1 area.

Integrative analysis of sex differences in the rapid antidepressant effects of ketamine in preclinical models for individualized clinical outcomes.

In major depressive disorder, women exhibit higher lifetime prevalence and different antidepressant response rates than men, which illustrates the importance of examining individual differences in the pathophysiology of depression and therapeutic response. In recent years, the consideration of sex in related preclinical research has thus gained interest-particularly in light of novel evidence for rapid-acting antidepressants. Notably, the literature recently revealed a higher sensitivity of females to the antidepressant effects of the N-methyl-D-aspartate receptor antagonist ketamine, in both baseline and preclinical conditions. Combined with its fast-acting and relatively sustained properties, this evidence highlights ketamine as a particularly interesting therapeutic alternative for this sensitive population, and supports the value in considering sex as a critical factor for improved individualized therapeutic strategies.

The Role of Early Growth Response 1 (EGR1) in Brain Plasticity and Neuropsychiatric Disorders.

It is now clearly established that complex interactions between genes and environment are involved in multiple aspects of neuropsychiatric disorders, from determining an individual's vulnerability to onset, to influencing its response to therapeutic intervention. In this perspective, it appears crucial to better understand how the organism reacts to environmental stimuli and provide a coordinated and adapted response. In the central nervous system, neuronal plasticity and neurotransmission are among the major processes integrating such complex interactions between genes and environmental stimuli. In particular, immediate early genes (IEGs) are critical components of these interactions as they provide the molecular framework for a rapid and dynamic response to neuronal activity while opening the possibility for a lasting and sustained adaptation through regulation of the expression of a wide range of genes. As a result, IEGs have been tightly associated with neuronal activity as well as a variety of higher order processes within the central nervous system such as learning, memory and sensitivity to reward. The immediate early gene and transcription factor early growth response 1 (EGR1) has thus been revealed as a major mediator and regulator of synaptic plasticity and neuronal activity in both physiological and pathological conditions. In this review article, we will focus on the role of EGR1 in the central nervous system. First, we will summarize the different factors influencing its activity. Then, we will analyze the amount of data, including genome-wide, that has emerged in the recent years describing the wide variety of genes, pathways and biological functions regulated directly or indirectly by EGR1. We will thus be able to gain better insights into the mechanisms underlying EGR1's functions in physiological neuronal activity. Finally, we will discuss and illustrate the role of EGR1 in pathological states with a particular interest in cognitive functions and neuropsychiatric disorders.

Prediction of individual differences in fear response by novelty seeking, and disruption of contextual fear memory reconsolidation by ketamine.

Only a portion of the population exposed to trauma will develop persistent emotional alterations characteristic of posttraumatic stress disorder (PTSD), which illustrates the necessity for identifying vulnerability factors and novel pharmacotherapeutic alternatives. Interestingly, clinical evidence suggests that novelty seeking is a good predictor for vulnerability to the development of excessive and persistent fear. Here, we first tested this hypothesis by analyzing contextual and cued fear responses of rats selected for their high (high responders, HR) or low (low responders, LR) exploration of a novel environment, indicator of novelty seeking. While HR and LR rats exhibited similar sensitivity to the shock and cued fear memory retention, fewer extinction sessions were required in HR than LR animals to reach extinction, indicating faster contextual and cued memory extinction. In a second part, we found an effective disruption of contextual fear reconsolidation by the N-methyl-d-aspartate receptor antagonist ketamine, associated with a down-regulation of early growth response 1 (Egr1) in the hippocampal CA1 area, and up-regulation of brain-derived neurotrophic factor (Bdnf) mRNA levels in the prelimbic and infralimbic cortices. Altogether, these data demonstrate a link between novelty seeking and conditioned fear extinction, and highlight a promising novel role of ketamine in affecting established fear memory.