NEUROPLASTICITY

PRESENTER: DR. CAROLINE DIAS CHAIRPERSON: DR. ANUPAMA

Plasticity was first applied to behavior in 1890

by William James in The Principles of Psychology.

The first person to use the term neural

plasticity appears to have been the Polish neuroscientist Jerzy Konorski

INTRODUCTION DEFINITION: The term is used for description of either

functional or structural changes of neurons and glial cells that occur in developing brain, as well as in the adult brain in order to adjust to external or internal stimuli. The role of neuroplasticity is widely recognized in

healthy development, learning, memory, and recovery from brain damage. During most of the 20th century, the general

consensus among neuroscientists was that brain

INTRODUCTION This belief has been challenged by findings

revealing that many aspects of the brain remain plastic even into adulthood. However, studies determined that environmental

changes could alter behavior and cognition by modifying connections between existing neurons and via neurogenesis in the hippocampus and other parts of the brain, including the cerebellum Decades of research have now shown that

substantial changes occur in the lowest neocortical processing areas, and that these changes can profoundly alter the pattern of neuronal activation in response to experience.

TYPES OF NEUROPLASTICITY Evolutionary plasticity: Reactive plasticity: Adaptive plasticity: Reparation plasticity:

STRUCTURAL BASIS OF NEUROPLASTICITY Neuronal plasticity in adult brain is manifested at

the cellular level by modification of dendritic growth, axonal sprouting, synaptic remodelling and creation of new synapses. This is closely linked with neurogenesis i.e. birth of new neurons

The most robust cell proliferation occurs in the

ventricles of forebrain near the olfactory bulbs

The second and the most consistent area showing

genesis of neurons is the dentate gyrus (DG) of hippocampus The hippocampus is critical to formation of new

memory Hence hippocampal neurogenesis is critical for

flexibility and adaptibility

Two types of neuroplasticity seen in the hippocampus at the molecular level Production of new neurons in the dentate gyrus Structural remodelling of the mossy fibre terminals of CA3 region in the hippocampus In favourable conditions like environmental stimulation and exercise there is more neurogenesis in DG as well as more arboristaion of CA3 fibres Increased arborisation of these fibres underlies the ability to complex thinking and flexibility and adaptibility of cognitive processes

Cell division and cell genesis giving rise to glial

cells have been found in every part of the brain although they do not give rise to neurons Recent research has led to the discovery of brain

stem cells and it is now possible to isolate these stem cells from the adult brain

Using specific growth factors (eg. Fibroblast growth

factor and epidermal growth factor) it has been even possible to induce them to divide indefinitely in culture Once these cells are committed to become a

neuron. Growth factors like brain derived neurotrophic factor (BDNF) and insulin factor factor (IGF) play important roles in keeping the cells alive and encouraging them to mature and become functional

Two types of neuroplastic changes have been described: Acute neuroplasticity: This is mediated by excitatory neurotransmitter

system like glutamate Rapid neuronal activation by acute stress leads to stimulation of glutamate Glutamate opens up post synaptic ionotropic receptors increasing intracellular sodium.

This causes neuronal depolarisation that leads to

activation of NMDA receptors This results in influx of calcium ca++/calmodulin

dependent protein kinase Within minutes to hours, structural alterations at the

level of dendritic spines occurs giving rise to acute neural plasticity

Long term plasticity: Activated by an appropriate stimuli for a chronic

duration, different signal transduction pathways induce expression, phosphorylation and subsequent activation of cAMP reactive element binding (CREB) protein Activated CREB protein leads to expression of a number of neurotrophic factors that then helps in neurogenesis and remodelling of neurons The two most researched neurotrophic factors are brain derived neurotrophic factor (BDNF) and fibroblast growth factor-2 (FGF-2)

BDNF BDNF is a major physiological survival factor It exerts its neurotrophic action and neuroprotective

effect through a cascade composed of tyrosine kinase receptors mitogen activated protein (MAP) kinase signalling pathwayactivation of bcl-2 expression. Bcl-2 is a major antiapoptotic protein controlling the programmed cell death The balance between pro-apoptotic and antiapoptotic proteins (bcl-2) critically controls neurodegeneration In this way BDNF exerts its major neuroprotective

Neuroplasticity in the adult brain includes: Changes of dendritic functions: dendritic spines play an important role in neural

processing. The morphology of dendritic spines is very diverse. Changes in spine size and density are thought to reflect changes in the synaptic strength Reorganization of synapses: there are evidences of the capacity of the human

brain to achieve both functional and structural reorganization. Besides environmental and learning induced plasticity, morphological alterations in the adult

Long term potentiation: long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. one of the major cellular mechanisms that underlies learning and memory. enhances synaptic transmission improves the ability of two neurons, one presynaptic and the other postsynaptic, to communicate with one another across a synapse.

Long term depression: is an activity-dependent reduction in the efficacy of neuronal synapses lasting hours or longer. results mainly from a decrease in postsynaptic receptor density opposing process to LTP one of several processes that serves to selectively weaken specific synapses in order to make constructive use of synaptic strengthening caused by LTP necessary because, if allowed to continue increasing in strength, synapses would ultimately

SYNAPTIC PLASTICITY The development of new synapses, the activity

dependent changes in the strength of existing synapses and the elimination of unwanted synapses form the basis of synaptic plasticity. The synaptic plasticity could be the cellular basis of learning and memory. The synaptic plasticity has been studied in many brain regions most frequently in the hippocampus and lately amygdala.

SYNAPTIC PLASTICITY original theory of plasticity is called Hebbian

Plasticity: cells that fire together, wire together cells fire together across areas for a common mental function If there are two nearby neurons that often produce an impulse simultaneously, their cortical maps may become one Hebbian plasticity involves two mechanisms: long term potentiation long term depression. LTP and LTD are considered as crucial for information storage in the cell.

METAPLASTICITY A novel form of persistent plasticity is called

metaplasticity(the plasticity of synaptic plasticity). Metaplasticity is induced by synaptic or cellular activity, but it is not a change in the efficacy of normal synaptic transmission. Instead , it is manifested as a change in the ability to induce subsequent synaptic plasticity, such as LTP or LTD. Thus, metaplasticity is a higher-order of synaptic plasticity and is important.

ROLE OF STRESS ON PLASTICITY Stress : any environmental change, whether

internal or external that disturbs homeostasis. Activates both HPA axis and sympathetic nervous

system. Chronic stress, as a result of the hypersecretion of

cortisol, causes a decrease in serotonin turnover, partly as a consequence of increased metabolism of tryptophan Provokes the secretion of epinephrine and nor-

epinephrine by the sympathetic nervous system to

ROLE OF STRESS ON PLASTICITYBrain areas involved in the stress response include the Pre-frontal cortex Hippocamous Amygdala They undergo stress induced remodelling, which alters behavioural and physiological responses

I ) STRESS AND GLUCOCORTICOIDS: Glucocorticoids regulate gene expression via binding of ligand- activated glucocorticoid receptor to glucocorticoid- responsive elements Broad range of deleterious effects on the brain

which include: Inhibition of glucose uptake into neurons Participation in glutamatergic neurotoxicity Elevation of free calcium concentrations Oxygen radical generation Significant disruption of the mobilization of neurotrophins

Action occurs predominantly in the hippocampus

can cause damage of neurons in hippocampus and the medial prefrontal cortex Produce impairments in memory, damaging

physical and mental health Anxiety, depression and psychotic disorders can

result from such changes in the HPA axis activity

II ) STRESS EFFECTS ON NEUROPLASTICITY IN BRAIN STRUCTURES: Can alter signalling pathways in synaptic plasticity Modulate brain functions by changing the structure of neuron, synaptogenesis, neurogenesis and dendritic remodelling HIPPOCAMPUS Hippocampus learning and memory, contextual fear conditioning and neuroendocrine regulation Elevated activity and volume loss of the hippocampus, the orbital and the ventral cortex in depressive disorder are recurrently described in literature Reduced volume reduced neuronal complexity and connectivity

Resulting from global ischaemia and hypoglycemia Prolonged exposure to stress or exposure to

glucocorticoids can have adverse effects on the neuron survival in the hippocampus May contribute to deficits in executive performance, learning and cognition- mediated memory formation Hippocampal atrophy recurrent or major depressive disorder and post traumatic stress disorder Hippocampal volume reduction generally occurs after disease onset Increased neurodegeneration, reduced neuroprotection and neuronal repair are common pathological features of major depressive disorder

PRE-FRONTAL CORTEX: Stress has similar effects on neuroplasticity in the pre-frontal cortex The ventral striatum and nucleus accumbens are also involved in neuroplasticity, stress and mood disorders Impaired function in them may explain the anhedonia and reduction in goal-seeking behaviour that is observed in depressive patients

AMYGDALA: In contrast to hippocampal and pre-frontal lobe change, chronic stress causes hypertrophy of neurons in the amygdala Hypertrophy of amygdala could underlie increased learning and memory in the context of stress induced emotional arousal Thus it may explain the indelible memories in posttraumatic stress disorders (PTSD) It may also be important in pathophysiology of anxiety disorders and depression Increased arborisation in amygdala may enhance emotional states or disrupt normal processing of emotional responses

III) GLUTAMATERGIC TOXICITY: Stress rapid increase in glutamate efflux in the pre-frontal cortex and the hippocampus Increased glutamate in synapse increased calcium within the cytoplasm overactivity of the calcium dependent enzymes cytoskeletal degeneration, protein malformation and oxygen radical generation atrophy or death of the neurons Different insults such as hypoxia- ischaemia, seizure and hypoglycemia can activate this pathway

MITOCHONDRIA IN NEUROPLASTICITY Mitochondrial electron transport chain generates

ATP that is essential for the survival of neurons and other cells Additional roles: Thermogenesis production of reactive oxygen species(ROS) regulation of intracellular calcium Cytoprotection developmental and synaptic plasticity arbitration of neuronal cell death

MITOCHONDRIA IN NEUROPLASTICITY Dysfunction could lead to cell death by the resulting

low ATP levels, overproduction of free radicals and initiation of apoptosis or other damage caused by leakage of macromolecules Mitochondria are the major source of cellular ROS potentially highly damaging but also involved in signal transduction pathways The regulation of synaptic plasticity is extremely energy expensive Mitochondria are transported to regions with high metabolic demands such as pre- synaptic terminals

Movement of mitochondria in the dendritic

protrusions correlates with the developmental and morphological plasticity of dendritic spines Apoptotic cascades can be activated locally in

synapses and dendrites (synaptic apoptosis) Synaptic loss and neuronal death in all

neurodegenerative disorders that involve excess activation of ionotropic glutamate receptors are caused by this mechanism Mitochondria can be integrally involved in the

general processes of synaptic plasticity both postsynaptic and presynaptic

Disturbed energy metabolism and glutamate may

be involved in neuronal death leading to neurodegenerative disorders Damage to mitochondria is caused primarily by

ROS produced by the mitochondria themselves Dysfunctions may contribute to pathogenesis of

Alzheimers disease, Parkinsons disease and Huntingtons disease, stroke, amyotrophic lateral sclerosis and psychiatric disorders such as schizophrenia, depressive disorder and bipolar disorder

BIOLOGICAL HYPOTHESIS OF DEPRESSIONMONOAMINE HYPOTHESIS OF DEPRESSION: Classic hypothesis- proposed that depression may be produced by a serotonin or nor-epinephrine deficiency Soon it became evident that this hypothesis in its original form could not explain all of the effects of antidepressants Revised monoamine theory monoamine systems are only modulating other brain neurobiological systems that have more primary role in depression

New theories about the pathophysiology of

depression and the action of antidepressant treatment reveal that mood disorders are caused by the structural or functional changes in particular molecules and signalling pathways in the brain

Antidepressants function by counteracting these

molecular changes

NEUROTROPHIC HYPOTHESIS OF DEPRESSION: Vulnerability to depression can arise as a result of neuronal damage eg. After chronic stress , long term high levels of glucocorticoids, hypoglycemia, ischaemia, effects of neurotoxins The therapeutic effects of antidepressants consist of

increased function of the noradrenergic or serotonergic system Leads to increased activity of transcription factor

CREB, higher expression of neurotrophin BDNF and increased neuronal plasticity

NEUROPLASTICITY HYPOTHESIS: Impaired mechanisms of neuroplasticity are core

pathophysiological features of this disorder chronic stress is an important factor in the

development of this impairment and long term treatment antidepressants leads to modulation of impaired mechanisms of neuroplasticity

NEUROGENESIS HYPOTHESIS: Depression can arise from hippocampal apoptosis and that an array of antidepressants ultimately work by stimulating such neurogenesis Antidepressants like fluvoxamine and tianeptine with

opposite impact on brain serotonin have been studied in detail MITOCHONDRIAL DYSFUNCTION HYPOTHESIS: Deficits in mitochondrial function play an important role in various aspects of mood disturbances

NETWORK HYPOTHESIS: Depressive disorder might represent disturbances in the information processing of the brain, rather than in the individual chemical balance of signalling molecules Neurotrophins act as critical tools in the process whereby environmental conditions guide neuronal networks to better adapt to the environment Emphasizes the importance of environmental information (such as social communication) in the recovery of the brain functions during treatment of mood disorders Combination of psychotherapy and pharmacothrapy gives rise to better outcomes

ANTIDEPRESSANTS AND NEUROPLASTICITY: Antidepressants affect learning and memory in animal models and enhance structural plasticity and hippocampal neurogenesis Antidepressants can directly modulate glutamatergic

neurotransmision through NMDA or AMPA receptors An intimate relationship exists between regulation of

monoaminergic and glutamatergic neurotransmission and antidepressant effects Converging lines of evidence demonstrate action of

Tianeptine (serotonin reuptake enhancer SSRE) on

Tianeptine prevents or reverses neurotransmission

in structural and cellular changes in the brain and normalizes disrupted glutamatergic neurotransmission in the hippocampus , amygdala and the cortex Fluvoxamine activates sigma 1 receptors at ERmitochondrial interface There is robust evidence that antidepressants

increase signalling pathways related to neuroplasticity by upregulation of cAMP/PKA/CREB cascade Long term antidepressant treatment enhances

neuroplasticity by upregulation of expression of many neurotrophic factors, especially of BDNF in the

MOOD STABILIZERS AND NEUROPLASTICITY: Affect multiple sites in intracellular signalling pathways Molecular and cellular targets of mood stabilizers include enzymes inhibited by lithium, valproate and carbamazepine (sodium channels, adenosine receptors, adenylate cyclase) and components of signalling pathways regulated by multiple drugs (protien kinase C , cAMP) Both lithium and valproate have neuroprotective effects based on protection from glutamatergic neurotoxicity on activation of cell survival factors such as protein kinase B pathway and on induction of neurotrophic and neuroprotecticve proteins

Mood stabilizers exert major effects on the

mitochondrial functions Chronic administration of lithium increases concentration of antiapoptotic protein Bcl-2 , reduces levels of the proapoptotic protein p53 Lithium also induces changes in activity of the respiratory chain complexes Activation of complexes I+II and complexes II+III were increased by lithium Lithium produces a reversal of illness-related atrophy The mitochondria-controlled process of oxidative damage could be a significant therapeutic target for treatment of bipolar disorder with mood- stabilizing drugs

BRAIN INJURY AND NEUROPLASTICITY: In the last 5 years, a striking number of neurological diseases and conditions have been shown to affect neurogenesis, especially in the hippocampus. Many of these new cells die, but some survive and, as a result of the epileptic state, these new cells migrate to the wrong place in the hippocampus and appear to differentiate incorrectly. These incorrectly generated new neurons have been speculated to play a role in the persistence of certain types of abnormal behavior and pathology By understanding how neurogenesis normally occurs to generate healthy neurons, it is hoped that this aberrant neurogenesis could be blocked or perhaps the aberrantly generated cells could be trained to wire up correctly.

STROKE, NEURODEGENRATIVE DISORDERS AND NEUROPLASTICITY: Cerebral stroke also results in a striking increase in the proliferation of new cells in the hippocampus, but most of these cells die soon thereafter. In addition, in certain types of stroke (like ischemia), there is loss of cells in areas of the brain that do not normally give rise to new neurons, and thus offer little hope for repair. Quite remarkably, more recent studies have revealed that, in fact, the brain is inducing repair by bringing new cells in from areas of the brain that do have stems cells and directing them to the sites of damage.

While with severe strokes, this microrepair is not

enough to reverse the damage, it is likely that this microrepair system is adequate to protect, prevent, and repair the brain after small, often-unrecognized strokes. Some of this repair is likely to be behind the oftenobserved remarkable though quite variable recovery that occurs after many strokes. Growth factors like EGF and FGF are now being used to try to enhance the intrinsic repair process, and with encouraging results.

The principle strategy is to learn enough about the

factors that regulate each of the components of neurogenesis in order to control cell proliferation (making more cells), migration (getting the cells to places where they are needed), and differentiation (turning the cells into the type of cell that is needed) For diseases of the brain and spinal cord, this will require more knowledge about which cells are affected in a disease, as well as knowing more about the factors that regulate the components of neurogenesis: For depression, epilepsy, and stroke, which are diseases that involve the hippocampus (a structure where neurogenesis does occur), the most straightforward strategy would be to induce more

In diseases like HD and PD, where very specific cell

types die to cause the symptoms, the best strategy would be to induce the local dividing cells to proliferate and then differentiate in small spine neurons, in the case of HD, and dopamine neurons, in the case of PD. In diseases like spinal cord injury or multiple sclerosis, the strategy may not be to make endogenous cells, become neurons, but rather to ensheath oligodendrocytes. Since the endogenous cells already have the capacity to make these cells at low frequency in the intact spinal cord, the task will be to enhance the endogenous capacity.

EPILEPSY AND NEURPLASTICITY: Slowly progressing changes in neural circuitry following an initial precipitating event like head injury, febrile convulsion, infections or still unknown causes have been postulated to invoke kindling- a phenomenon of neural plasticity- and progress to give rise to epilepsy Kindling is a process of induction of progressive and permanent increase susceptibility in neural circuits by application of repeated subthreshold stimuli. This involves a progressive sequence of long lasting changes in molecular and cellular level, which gradually but permanently changes the neural connectivity It results in progressive decrease in seizure threshold

ECT AND NEUROPLASTICITY: ECT is used in the treatment of severe depression one of the most common side effects is a marked (though transient) disorder of memory function Rats given a 10-day course of electroconvulsive stimulation similar to that used in psychiatric practice showed a large rise in the size of the evoked potential that strongly resembles long-term potentiation. it is known that repeated induction of long-term potentiation eventually raises synaptic strengths to a maximum level, beyond which they cannot be increased experimentally

occlusion of long term potentiation suggests that the

changes after electroconvulsive stimulation reflects true induction of long-term potentiation, and that the failure of subsequent tetanization to induce further long-term potentiation is due to saturation of synaptic strengths. This raises the possibility that the amnesia seen after repeated ECT arises because synaptic strengths are pushed to their ceiling levels, thus preventing the formation of new memories until such time as the strengths decay back to a baseline level Because induction of long-term potentiation depends on NMDA receptors, an NMDA antagonist might also be expected to block the post ECT changes in evoked potentials.

pretreatment with ketamine (a potent NMDA

antagonist) may prevent the electroconvulsive stimulation-associated increase in evoked response size and thus ameliorate amnesia after ECT in humans Besides its benefits for patients undergoing ECT,

such a finding would constitute important support for the hypothesis that changes in synaptic strength mediate memory storage. neuroplasticity effects in the hippocampus neurogenesis in the dentate gyrus, and synaptogenesis in the CA1 area. Perforated and

NEUROPLASTICITY IN THE TREATMENT OF AUTISTIC DISORDERS: In autism, certain areas of the brain are often impaired leading to problems in emotional control, memory, learning capacity, and perceptions. The hippocampus (involved in short to long-term memory processing and spatial navigation which helps with memory of surrounding environment), and amygdala (involved in emotional memory, mood, etc.) are part of the limbic system. When this area of the limbic brain is impaired emotional instability, poor self-regulation, selfstimulatory behaviors and rigidity in thought and behavior can become manifest

Another area of dysfunction is the prefrontal cortex

which is involved in decision making and short-term memory. The inability of these brain regions to synchronize

appropriately adds to the behavior and cognitive problems prevalent in autism. However, through neuroplasticity the brain can adapt

and change and improvements can be seen in many individuals on the autism-spectrum undergoing consistent autism treatments such as biomedical intervention including diet, supplements, methylation (Methyl-B12), hyperbaric oxygen therapy, and

The principles of neuroplasticity are also utilized by

therapist working on the core behavioral and social issues of those with autism as well The key element for all of these autism treatments is repetition and consistency overtime to help increase new neural connections and pathways for improved and synchronized brain function.

SCHIZOPHRENIA AND NEUROPLASTICITY: Considering schizophrenia as a disorder of neuroplasticity permits integration of competing neurochemical and neurodevelopmental hypotheses. Recent advances have linked the pathophysiology of schizophrenia with abnormalities of the glutamate neurotransmitter system. Elements of glutamergic neurotransmission implicated in schizophrenia, including glutamate receptors and receptor-associated molecules, have critical roles in long-term potentiation, a molecular correlate of neuroplasticity.

Effects of Antipsychotics on Neurotropic Factors A large and growing body of literature confirm that neurotropins such as nerve growth factor (NGF) and BDNF are reduced in treatment-naive schizophrenia. deficit of neurotropins in schizophrenia may be related to the reduced neuropil and atrophic cortical and subcortical changes in schizophrenia. BDNF, for example, has a strong influence on hippocampal volume, known to be diminished in schizophrenia FGAs and SGAs have different effects on neurotropins in schizophrenia

In animal experiments, haloperidol causes

pronounced reductions in NGF and BDNF, which is reversed by olanzapine and risperidone. In a study of first-episode and chronic schizophrenia, NGF was found to be reduced by more than 60% in drug-naive patients, but it was increased by risperidone. However, patients chronically treated with haloperidol and other FGAs were found to have NGF as low as patients with untreated schizophrenia. Quetiapine was found to increase NGF acutely in rats, which has been shown to stimulate BDNF expression

neuroplastic effects of the FGAs appear to be restricted

to inducing proliferation of receptors in the basal ganglia, with hyperplasia of the striatum and changes in the morphology and the number of synapses, mainly of the glutamatergic type. SGAs also influence neuroplasticity, but less in the

striatum and more in brain regions implicated in schizophrenia such as the prefrontal and limbic areas. SGAs may enhance synaptic connectivity, which could

lead to repairing the diminished neuropil in the cortex of people with schizophrenia.

A total of 50 hours of neuroplasticity-based

computerized cognitive training appears sufficient to drive improvements in verbal learning/memory and cognitive control that endure 6 months beyond the intervention but a higher dose and more broad-spectrum training may be necessary to drive enduring gains in processing speed and global cognition. Training-induced cognitive improvement is related to enhanced functioning at 6 months

TRANSCRANIAL MAGNETIC STIMULATION: rTMS has primarily been used as an assessment tool for motor function an increasing number of studies are using TMS as a tool to directly induce plasticity and improve motor function by selective stimulation of the cerebral cortex Enhancement of excitability of the motor cortex seems to speed up procedural learning TMS conjunction with physical, occupational, behavioral or other rehabilitative therapies in order to enhance their beneficial effects for patients recovering from brain Injury. Preactivation of a given cortical region prior to more

DEEP BRAIN STIMULATION: Two generally hypothesized mechanisms of action are creates a functional lesion via inhibition within the stimulated region eg. : immediate effects of some applications of deep brain stimulation (e.g. effects on motor function in Parkinson's disease) activates the neuronal network connected to the stimulated region, leading to modulation of pathological network activitye eg : while the latter may be more consistent with deep brain stimulationinduced gradual effects (e.g. circuit retraining) as seen in neuropsychiatric disorders. This observed dendritic plasticity may underlie the

RELAXATION TECHNIQUES AND MEDITATION: meditation strengthens the health of the nervous system, leading to stronger physical and emotional health Intellectual activities strengthen the neural circuits of the frontal lobe, which has more neural interconnections than any other lobe Studies also suggest that a strong frontal lobe is linked with self-management in terms of lifestyle, diet, exercise routines and emotional control. All forms of exercise enhance neural functioning Studies show that exercise can help restore brain circuits damaged by brain lesions and strokes; it also repairs and protects the brain from stress by enhancing neural plasticity. It slows down loss of brain tissues

Faith healing: Research shows that a moderate optimistic illusion is essential for motivation and mental health. Highly optimistic people activate parts of the anterior cingulate that control anxiety, depression, rage; this is the same area that nurtures compassion and social consciousness. one 's deliberate choice for optimism induces a change in the neural circuitry

CONCLUSION Environmental stress and genetic risk variants

interact with each other in a complex manner to alter neural circuitry and evoke illness Developmental and structural changes in neural networks are necessary conditions for vulnerability to the development of pathological states of mind Mild dysfunction of some mitochondrial functions might be the basis for homeostatic imbalance in synapses during episodes of anxiety, depression, mania or the appearance of morbid states

CONCLUSION Regulation of critical intracellular signalling

pathways plays a critical role in higher order brain functions, which are altered in mood disorders Structural deviations in neural networks and disturbances of signal transduction in neurons contribute to the development of psychiatric disorders Novel biomarkers and predictors of efficiency of pharmacotherapy may be discovered on the basis of this research

THANK YOU