Research

Introduction

The research of Dr. Alachkar focuses on understanding the neurobiology of neurological and psychiatric disorders and identifying therapeutic targets for optimal treatment. Particularly, we are interested in searching for novel treatment for Parkinson’s Disease, Schizophrenia, Depression, Postpartum Depression, Anxiety. Our approaches range from genetic to  molecular, to chemical to behavioral studies.

Prenatal Micronutrients Programming of Psychiatric Disorders (Schizophrenia & Autism)

Nutritional aversive conditions during pregnancy such as famine or over-nutrition can significantly disrupt fetal development and contribute to long-term cognitive deficits in the offspring. We focus our studies in this project on how these deficits result primarily from dysregulations of one-carbon metabolism and consequently that imbalances in prenatal diet are major factors in the etiology of neuropsychiatric disorders such as schizophrenia and autism.

We use animal models to investigate how the dietary manipulation of one-carbon metabolism during gestational stage can program the brain functions, alter neurodevelopment and shape the behavioral phenotypes in the offspring. The one-carbon pathway components may prompt new therapeutic options for the treatment of psychiatric disorders.


Novel Approaches for the Treatment of Parkinson’s Disease

Parkinson’s disease is characterized by degeneration of dopaminergic cells in the basal ganglia.  Dopamine-replacement therapy, mainly with L-DOPA, is currently the most effective treatment.  However, long-term treatment with dopaminergic drugs has several side effects, including dyskinesia. Better understanding of the chemical mechanisms underlying the symptoms of Parkinson’s disease may lead to the development of new strategies for the treatment of PD.

Since the symptoms of Parkinson’s disease are attributed to overactivity of the outputs of the basal ganglia (medial globus pallidus (GPm) and substantia nigra pars reticulata (SNr)), our research focuses on searching for compounds that can improve the symptoms of Parkinson’s disease through reducing the overactivity of the output structures of the basal ganglia. Such agents can reduce the excitability of neurones of the indirect striatal pathway to increase the activity of the lateral globus pallidus, or act directly on the output regions to reduce the activity of the SNr and/or the GPm.


Neuronal Circuits of Maternal Care and Postpartum Depression

 

The mother-infant relationship is of particular importance because it forms the earliest experience of social interaction, which profoundly impacts cognitive, emotional and social development. Poor maternal care, such as neglect, has been steadfastly linked with subsequent increased offspring’s risk for deficits in cognitive performance, academic achievement, and psychopathology such as antisocial and aggressive behaviors. This project focuses on understanding the neurocircuits that regulate the initiation of maternal behavior and postpartum mood disorders such as postpartum depression.

Oxytocin is known as the key regulator of the onset of maternal behaviors. Very little is known, however, about the hypothalamic circuits that are regulated by oxytocin to induce the onset and termination of maternal care. We showed that another neuropeptide, melanin concentrating hormone (MCH), plays an important role in regulating maternal behavior and postpartum mood. We integrate neuroanatomical, pharmacological and genetic approaches to investigate role of oxytocin- MCH neurocircuit in the regulation of maternal behavior and postpartum depression.


Transgenerational impacts of Stress

Exposure to prenatal stress can disrupt neurodevelopment and cause long-lasting changes on the brain structure and function. “Natural experiments” have taught us lessons about how parental exposure to war-related trauma, natural disaster, and abuse can increase the incidence of psychiatric diseases such as depression, anxiety, and PTSD in the offspring. We are interested in studying, in mice, how the transgenerational stress (existential threat) programs the brain and shapes the behaviors of the first and second generations of offspring.


Approaches 

Mice that have genes deleted (knock out) or genes added (knock in) are used to study the role of specific genes in normal and abnormal behaviors. We examine mouse behaviors using wide range of assays including: sociability, social novelty, open filed, elevated maze, forced swim, sucrose preference, different types of memory (working memory using T-maze, novel object recognition, novel location recognition, cued and contextual fear conditioning).

We dissect the brain to analyze the changes in neurotransmitter circuit, metabolites, gene expression.  We utilize immunohistochemistry, in situ hybridization, LC-MS analysis, qPCR and other chemical methods.