Faculty Bibliography

Seizure incidence is increased in Alzheimer's disease (AD) patients and mouse models, and treatment with the antiseizure drug levetiracetam improves cognition. We reported that one mechanism by which seizures can exert persistent effects on cognition is through accumulation of ΔFosB, a transcription factor with a long half-life. Even the infrequent seizures that spontaneously occur in transgenic mice expressing human amyloid precursor protein (APP) lead to persistent increases in ΔFosB in the hippocampus, similar to what we observed in patients with AD or temporal lobe epilepsy. ΔFosB epigenetically regulates expression of target genes, however, whether ΔFosB targets the same genes when induced by seizures in different neurological conditions is not clear. We performed ChIP-sequencing to assess the repertoire of ΔFosB target genes in APP mice and in pilocarpine-treated wildtype mice (Pilo mice), a pharmacological model of epilepsy. These mouse models allowed us to compare AD, in which seizures occur in the context of high levels of amyloid beta, and epilepsy, in which recurrent seizures occur without AD-specific pathophysiology. Network profiling of genes bound by ΔFosB in APP mice, Pilo mice, and respective control mice revealed that functional domains modulated by ΔFosB in the hippocampus are expanded and diversified in APP and Pilo mice (vs. respective controls). Domains of interest in both disease contexts involved neuronal excitability and neurotransmission, neurogenesis, chromatin remodeling, and cellular stress and neuroinflammation. To assess the gene targets bound by ΔFosB regardless of seizure etiology, we focused on 442 genes with significant ΔFosB binding in both APP and Pilo mice (vs. respective controls). Functional analyses identified pathways that regulate membrane potential, glutamatergic signaling, calcium homeostasis, complement activation, neuron-glia population maintenance, and chromatin dynamics. RNA-sequencing and qPCR measurements in independent mice detected altered expression of several ΔFosB targets shared in APP and Pilo mice. Our findings indicate that seizure-induced ΔFosB can bind genes in patterns that depend on seizure etiology, but can bind other genes regardless of seizure etiology. Understanding the factors that underlie these differences, such as chromatin accessibility and/or abundance of co-factors, could reveal novel insights into the control of gene expression in disorders with recurrent seizures.

The collaborative effort of an international research team from the Early Career Psychiatrists section of the World Psychiatry Association has brought about an easy-to-use, quick and stepwise mental health care toolkit for the identification and appropriate referral of those in need of mental health care during the pandemic. This simple guide can be applied in the general outpatient setting and is catered for all healthcare professionals, regardless of their expertise within the mental health field with minimal training. It is our hope that by incorporating this toolkit into our daily clinical care during the pandemic for high-risk patients and patients with non-specific complaints, we will be able to bridge the mental health gap present in our society.

Neurogenesis in the adult hippocampus was rediscovered in the 1990's after being reported in the 1960's. Since then, thousands upon thousands of laboratories have reported on the characteristics and presumed functional significance of new neurons in the adult brain. In 1999, we reported that mental training with effortful learning could extend the survival of these new cells and in the same year, others reported that physical training with exercise could increase their proliferation. Based on these studies and others, we developed MAP Train My Brain™, which is a brain fitness program for humans. The program combines mental and physical (MAP) training through 30-min of effortful meditation followed by 30-min of aerobic exercise. This program, when practiced twice a week for eight weeks reduced depressive symptoms and ruminative thoughts in men and women with major depressive disorder (MDD) while increasing synchronized brain activity during cognitive control. It also reduced anxiety and depression and increased oxygen consumption in young mothers who had been homeless. Moreover, engaging in the program reduced trauma-related cognitions and ruminative thoughts while increasing self-worth in adult women with a history of sexual trauma. And finally, the combination of mental and physical training together was more effective than either activity alone. Albeit effortful, this program does not require inordinate amounts of time or money to practice and can be easily adopted into everyday life. MAP Training exemplifies how we as neuroscientists can take discoveries made in the laboratory out into the world for the benefit of others.

Huntington's disease (HD) is a genetic neurodegenerative disorder, caused by an expanded CAG repeat in the gene encoding the huntingtin protein. At the premanifest phase, before motor symptoms occur, psychiatric and emotional disorders are observed with high prevalence in HD patients. Agitation, anxiety and irritability are often described but also depression and/or apathy, associated with a lack of emotional control. The aim of the present study was to better circumscribe and understand the emotional symptoms and assess their evolution according to the progression of the disease using a transgenic HD model, BACHD rats, at the age of 4, 12 and 18 months. To achieve this goal, we confronted animals to two types of tests: first, tests assessing anxiety like the light/dark box and the conflict test, which are situations that did not involve an obvious threat and tests assessing the reactivity to a present threat using confrontation with an unknown conspecific (social behavior test) or with an aversive stimulus (fear conditioning test). In all animals, results show an age-dependent anxiety-like behavior, particularly marked in situation requiring passive responses (light/dark box and fear conditioning tests). BACHD rats exhibited a more profound alteration than WT animals in these tests from an early stage of the disease whereas, in tasks requiring some kind of motivation (for food or for social contacts), only old BACHD rats showed high anxiety-like behavior compared to WT, may be partly due to the other symptoms' occurrence at this stage: locomotor difficulties and/or apathy.

Most odors are not composed of a single volatile chemical species, but rather are mixtures of many different volatile molecules, the perception of which is dependent on the identity and relative concentrations of the components. Changing either the identity or ratio of components can lead to shifts between configural and elemental perception of the mixture. For example, a 30/70 ratio of ethyl isobutyrate (odorant A, a strawberry scent) and ethyl maltol (odorant B, a caramel scent) is perceived as pineapple by humans - a configural percept distinct from the components. In contrast, a 68/32 ratio of the same odorants is perceived elementally, and is identified as the component odors. Here, we examined single-unit responses in the anterior and posterior piriform cortex (aPCX and pPCX) of mice to these A and B mixtures. We first demonstrate that mouse behavior is consistent with a configural/elemental perceptual shift as concentration ratio varies. We then compared responses to the configural mixture to those evoked by the elemental mixture, as well as to the individual components. Hierarchical cluster analyses suggest that in the mouse aPCX, the configural mixture was coded as distinct from both components, while the elemental mixture was coded as similar to the components. In contrast, mixture perception did not predict pPCX ensemble coding. Similar electrophysiological results were also observed in rats. The results suggest similar perceptual characteristics of the AB mixture across species, and a division in the roles of aPCX and pPCX in the coding of configural and elemental odor mixtures.

Maternal stress during pregnancy is associated with increased risk of psychiatric disorders in offspring, but embryonic brain mechanisms disrupted by prenatal stress are not fully understood. Our lab has shown that prenatal stress delays inhibitory neural progenitor migration. Here, we investigated redox dysregulation as a mechanism for embryonic cortical interneuron migration delay, utilizing direct manipulation of pro- and antioxidants and a mouse model of maternal repetitive restraint stress starting on embryonic day 12. Time-lapse, live-imaging of migrating GAD67GFP+ interneurons showed that normal tangential migration of inhibitory progenitor cells was disrupted by the pro-oxidant, hydrogen peroxide. Interneuron migration was also delayed by in utero intracerebroventricular rotenone. Prenatal stress altered glutathione levels and induced changes in activity of antioxidant enzymes and expression of redox-related genes in the embryonic forebrain. Assessment of dihydroethidium (DHE) fluorescence after prenatal stress in ganglionic eminence (GE), the source of migrating interneurons, showed increased levels of DHE oxidation. Maternal antioxidants (N-acetylcysteine and astaxanthin) normalized DHE oxidation levels in GE and ameliorated the migration delay caused by prenatal stress. Through convergent redox manipula-tions, delayed interneuron migration after prenatal stress was found to critically involve redox dysregulation. Redox biology during prenatal periods may be a target for protecting brain development.

Local translation can support memory consolidation by supplying new proteins to synapses undergoing plasticity. Translation in adult forebrain dendrites is an established mechanism of synaptic plasticity and is regulated by learning, yet there is no evidence for learning-regulated protein synthesis in adult forebrain axons, which have traditionally been believed to be incapable of translation. Here we show that axons in the adult rat amygdala contain translation machinery, and use translating ribosome affinity purification (TRAP) with RNASeq to identify mRNAs in cortical axons projecting to the amygdala, over 1200 of which were regulated during consolidation of associative memory. Mitochondrial and translation-related genes were upregulated, whereas synaptic, cytoskeletal, and myelin-related genes were downregulated; the opposite effects were observed in the cortex. Our results demonstrate that axonal translation occurs in the adult forebrain and is altered after learning, supporting the likelihood that local translation is more a rule than an exception in neuronal processes.

Large-scale functional connectome formation and re-organization is apparent in the second trimester of pregnancy, making it a crucial and vulnerable time window in connectome development. Here we identified which architectural principles of functional connectome organization are initiated prior to birth, and contrast those with topological characteristics observed in the mature adult brain. A sample of 105 pregnant women participated in human fetal resting-state fMRI studies (fetal gestational age between 20 and 40 weeks). Connectome analysis was used to analyze weighted network characteristics of fetal macroscale brain wiring. We identified efficient network attributes, common functional modules and high overlap between the fetal and adult brain network. Our results indicate that key features of the functional connectome are present in the second and third trimesters of pregnancy. Understanding the organizational principles of fetal connectome organization may bring opportunities to develop markers for early detection of alterations of brain function.SIGNIFICANCE STATEMENTThe fetal to neonatal period is well known as a critical stage in brain development. Rapid neurodevelopmental processes establish key functional neural circuits of the human brain. Prenatal risk factors may interfere with early trajectories of connectome formation and thereby shape future health outcomes. Recent advances in MRI have made it possible to examine fetal brain functional connectivity. In this study, we evaluate the network topography of normative functional network development during connectome genesis in utero Understanding the developmental trajectory of brain connectivity provides a basis for understanding how the prenatal period shapes future brain function and disease dysfunction.

This tutorial introduces recent developments in precision medicine for estimating treatment decision rules. The objective of these developments is to advance personalised healthcare by identifying an optimal treatment option for each individual patient based on each patient's characteristics. The methods detailed in this tutorial define composite variables from the patient measures that can be viewed as 'biosignatures' for differential treatment response, which we have termed 'generated effect modifiers'. In contrast to most machine learning approaches to precision medicine, these biosignatures are derived from linear and non-linear regression models and thus have the advantage of easy visualisation and ready interpretation. The methods are illustrated using examples from randomised clinical trials.

Gender is one of the central categories organizing children's social world. Clear patterns of gender development have been well-documented among cisgender children (i.e., children who identify as a gender that is typically associated with their sex assigned at birth). We present a comprehensive study of gender development (e.g., gender identity and gender expression) in a cohort of 3- to 12-y-old transgender children (n = 317) who, in early childhood, are identifying and living as a gender different from their assigned sex. Four primary findings emerged. First, transgender children strongly identify as members of their current gender group and show gender-typed preferences and behaviors that are strongly associated with their current gender, not the gender typically associated with their sex assigned at birth. Second, transgender children's gender identity (i.e., the gender they feel they are) and gender-typed preferences generally did not differ from 2 comparison groups: cisgender siblings (n = 189) and cisgender controls (n = 316). Third, transgender and cisgender children's patterns of gender development showed coherence across measures. Finally, we observed minimal or no differences in gender identity or preferences as a function of how long transgender children had lived as their current gender. Our findings suggest that early sex assignment and parental rearing based on that sex assignment do not always define how a child identifies or expresses gender later.