Elevated peripheral proline is associated with psychiatric disorders, and there is evidence that proline is a neuromodulator. The proline dehydrogenase (PRODH) gene, which encodes the enzyme that catalyzes proline catabolism, maps to human chromosome 22q11.2, a region conferring risk of schizophrenia. In the Prodh-null mouse, an interaction between elevated peripheral proline and another 22q11.2 gene, catechol-O-methyltransferase (COMT), on neurotransmission and behavior has been reported. We explored the relationship between fasting plasma proline levels and COMT Val158Met genotype on symptoms (positive, negative and total) in schizophrenia patients. In an exploratory study we also examined symptom change in patients with bipolar disorder. There was a significant interaction between peripheral proline and COMT on negative symptoms in schizophrenia (P<0.0001, n=95). In COMT Val/Val patients, high proline was associated with low Scale for the Assessment of Negative Symptom (SANS) scores. In contrast, high proline was associated with high SANS scores in patients carrying a Met allele. The relationship between proline and COMT also appears to modify negative symptoms across psychiatric illness. In bipolar disorder, a significant interaction was also observed on negative-symptom change (P=0.007, n=43). Negative symptoms are intractable and largely unaddressed by current medications. These data indicate a significant interaction between peripheral proline and COMT genotype, influencing negative symptoms in schizophrenia and bipolar disorder. That high proline has converse effects on symptoms by COMT genotype, may have implications for therapeutic decisions.
Deficiencies in the adaptive immune system have been linked to anxiety-like behaviours and stress reactivity. Mice lacking T lymphocytes through knockout of the T cell receptor (TCR) β and δ chains were compared to wild type C57Bl/6 mice. Central stress circuitry gene expression was assessed following repeated restraint stress. TCRβ−/−δ−/− mice showed an increased baseline plasma corticosterone and exaggerated changes in stressrelated gene expression after repeated restraint stress. Sexual dimorphic stress responses were observed in wildtype C57Bl/6 mice but not in TCRβ−/−δ−/− mice. These data suggest that T cell-brain interactions influence sex-differences in CNS stress circuitry and stress reactivity.
Gene-environment interactions in the postnatal period have a long-term impact on neurodevelopment. To effectively model neurodevelopment in the mouse, we incorporated several validated behavioural tests to develop a behavioural pipeline that measures translationally relevant milestones of development in mice. The behavioral phenotype of 1060 wild type and genetically-modified mice was examined in parallel with structural brain imaging. The influence of genetics, sex, and early life stress on behaviour and neuroanatomy was determined using traditional statistical and machine learning methods. The results demonstrated that neuroanatomical diversity was primarily associated with genotype whereas behavioural phenotypic diversity was observed to be more susceptible to gene-environment interactions.
Decades of research have established the role of microbiota–brain communication in behaviour and brain function. Studies have shown that microbiota composition and diversity are influenced by a variety of factors including host genetics, diet, and other environmental exposures, with implications for the immunological and neurobiological development of the host organism. To further understand early-life interactions between environment, genetic factors, the microbiome and the central nervous system, we investigated the impact of postnatal stress in C57Bl/6 wild type and T-cell deficient mice on microbe–brain interactions and behaviour. Mice were exposed to immune challenge with lipopolysaccharide (LPS) at postnatal day (P) 3 and maternal separation at P9 (16 h overnight). Behavioural assessment of growth and development as well as behaviour (righting reflex, ultrasonic vocalizations in response to brief maternal separation, open field, sociability, and grooming) was conducted. Microbiota diversity and composition of fecal samples collected at P24 revealed reduced alpha diversity in T-cell-deficient mice as well as genotype- and stress-related taxa. Notably, integrated analyses of microbiota and behaviour in the context of immunocompromise revealed key behavioural related taxa that may be important to brain development. These findings are important to determining the influence of genetic and environmental factors on gut microbiota and advances our understanding microbiome–brain signaling pathways on neurodevelopment and behaviour.
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