Scientists suggest a new approach unraveling etiology and possible reversal of complex psychiatric disorders

The article is an collaborative research of scientists from apex Indian medical research institutions as All India Institute of Medical Sciences (AIIMS), New Delhi, National brain research centre, Manesar, and Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry and has been published in an internationally reputed peer-reviewed neuroscience research journal ‘Neurology, Psychiatry and Brain Research.

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Etiology of the complex psychiatric disorders remains elusive owing to unapproachability of intricate neural circuits in living human. Scientists from apex Indian medical research institutions as All India Institute of Medical Sciences (AIIMS), New Delhi, National brain research centre, Manesar, and Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Pondicherry,  have published the collaborative research work titled, “Induction-reversal modeling of psychiatric disorders by functional manipulation of habenular pathways in zebrafish”  in an internationally reputed peer-reviewed neuroscience research journal ‘Neurology, Psychiatry and Brain Research’ proposing the possible use of an emerging advanced neuroscience research technique optogenetics in transgenic zebrafish model for understanding genesis,  progression and possible reversal of various psychiatric disorders.  Optogenetics, an advance neuroscience research technique propagated by Karl Disseroth’s lab at Stanford University combines knowledge of optics and genetics to explore the function of specific neural circuits which may be functionally manipulated based on activation or inactivation of the specific ion channels in the targeted group of neurons by illumination of light.

The proposed model will lead to finding the basic solution regarding the complexity of psychiatric disorders stated Dr. Ashutosh Kumar, Assistant Professor in Department of Anatomy, JIPMER (Karaikal), Pondicherry. Further adding to the research outcomes Dr. Ashutosh Kumar explained that the optogenetics mediated inactivation of lateral subnucleus of dorsal habenular nuclei in transgenic zebrafish leads to freezing rather than flight response in fearful stimuli similar to indecisiveness shown by Post Traumatic Stress Disorder (PTSD) subjects facing acute stress.  Dysregulation of the emotional behavior forms the base of the psychiatric disorders like anxiety, depression, and PTSD hence functional manipulation of habenular nuclei and gradual increase and decrease in levels of stress may prove to be a basic model for induction and reversal of such psychiatric disorders.

Dr. Muneeb Faiq, Dr. Khursheed Raza and Dr. Subramnyam Dantham from AIIMS Optogenetics Study Group said that this is the first of its kind of study where a basic psychiatric disorder model using transgenic zebrafish and optogenetics has been proposed to unravel etiology and possible reversal of complex psychiatric disorders with functional manipulation of specific neural circuits.

Registered Pharmacist and Ph.D. Scholar, Vikas Pareek from NBRC, and Dr. Khursheed Raza and Dr. Pavan Kumar from AIIMS asserted that close anatomical and functional resemblance of the fish and human habenular neural circuits has led to the feasibility of a fish brain model for the complex human psychiatric disorders. Habenula is an evolutionarily conserved bilateral brain structure having a major role in adaptive behavior under aversive and fruitful conditions via regulation of brainstem aminergic neurotransmitters and neuromodulators. Optogenetic inactivation with the graded amount of stress in the lateral habenular descending pathway and medial habenular pathway may lead to two opposing character psychiatric disorders as mania and major depression stated the authors.

The conceptual basis of the hypothesis as stated by authors has been that the psychiatric disorders etiologically may be the stress adaptation response of the psychologically traumatized brain, and disease process may be reversed within unspecified limits with specialized interventional techniques and rehabilitation approaches. The proposed theory may prove to be beneficial for translational research aimed to develop efficient therapeutic modules for complex psychiatric disorders.

More information: Induction – reversal modeling of psychiatric disorders by functional manipulation of habenular pathways in zebrafish, Neurology, Psychiatry and Brain Research, Volume 24, June 2017, Pages 1-8, ISSN 0941-9500, http://dx.doi.org/10.1016/j.npbr.2016.12.003.

(http://www.sciencedirect.com/science/article/pii/S0941950016300203)

Abstract

The etiomechanism of psychiatric disorders is still poorly understood. Optogenetically induced changes in neural networks and consequent change of behavior in transgenic animals has provided a novel opportunity to develop animal models of various psychiatric disorders. We hereby propose zebrafish as a model organism based on the premise of its comprehensive similitude with the mammalian brain. The habenula is an evolutionarily conserved bilateral structure located at the interface of diencephalon, basal nuclei and brainstem working as a gateway between cortical-subcortical and brainstem structures. Many studies have suggested master role of habenula in control of adaptive behavior through regulation of brainstem aminergic nuclei. It is thought to function as a switchboard for regulating emotional behavior in conditions facing survival challenges. The dysregulation of the emotional behavior has been at the base of psychiatric disorders and a functional manipulation of specific habenular nuclei using optogenetics combined with incremental levels of stress challenge may prove to be a basic model for the genesis of psychiatric disorders. Conversely, reversing the manipulation, scaling down stress levels, and providing enriched environment may ease psychiatric symptoms. The present article has proposed a hypothesis on the development of a basic zebrafish model for the psychiatric disorders based on this concept. Such a model may be of great help in understanding the common mechanism involved in genesis and progression of various psychiatric disorders. The article has also elaborated on the operational mechanisms and validity of the methodology and has suggested an experimental design for the proposed study model.

Keywords: Habenular pathways; Optogenetic manipulation; Psychiatric disorders; Stress; Transgenic animal models