Suwarna Chakraborthy (PhD Scholar) presented her PhD work presentation titled "Depression-induced cognitive deficits: effect of modulation of glutamatergic transmission and brain stimulation reward".
Suwarna Chakraborty (PhD Scholar) presented the paper by Der-Avakian etal from Biological Psychiatry Jan 2014 entitled "Enduring Deficits in Brain Reward Function after Chronic Social Defeat in Rats: Susceptibility,Resilience, and Antidepressant Response"
Anhedonia, or diminished interest or pleasure in rewarding activities, characterizes depression and reflects deficits in brain reward circuitries. Social stress induces anhedonia and increases risk of depression, although the effect of social stress on brain reward function is incompletely understood.
This study assessed the following: 1) brain reward function in rats (using the intracranial self-stimulation procedure) and protein levels of brain-derived neurotrophic factor and related signaling molecules in response to chronic social defeat, 2) brain reward function during social defeat and long-term treatment with the antidepressants fluoxetine (5 mg/kg/day) and desipramine (10 mg/kg/day), and 3) forced swim test behavior after social defeat and fluoxetine treatment.
Social defeat profoundly and persistently decreased brain reward function, reflecting an enduring anhedonic response, in susceptible rats, whereas resilient rats showed no long-term brain reward deficits. In the ventral tegmental area, social defeat, regardless of susceptibility or resilience, decreased brain-derived neurotrophic factor and increased phosphorylated AKT, whereas only susceptibility was associated with increased phosphorylated mammalian target of rapamycin. Fluoxetine and desipramine reversed lower, but not higher, stress-induced brain reward deficits in susceptible rats. Fluoxetine decreased immobility in the forced swim test, as did social defeat.
These results suggest that the differential persistent anhedonic response to psychosocial stress may be mediated by ventral tegmental area signaling molecules independent of brain-derived neurotrophic factor and indicate that greater stress-induced anhedonia is associated with resistance to antidepressant treatment. Consideration of these behavioral and neurobiological factors associated with resistance to stress and antidepressant action may promote the discovery of novel targets to treat stress-related mood disorders.
Dr Jyothi Kakumanu (PhD Scholar) presented the paper from Biological Psychology by Keune et al., 2013 entitled "Approaching dysphoric mood: State-effects of mindfulness meditation on frontal brain asymmetry"
Meditation-based interventions reduce the relapse risk in recurrently depressed patients. Randomized trials utilizing neurophysiologic outcome measures, however, have yielded inconsistent results with regard to a prophylactic effect. Although frontal brain asymmetry, assessed through electroencephalographic (EEG) alpha activity (8–13 Hz), is indicative of approach vs. withdrawal-related response dispositions and represents a vulnerability marker of depression, clinical trials have provided mixed results as to whether meditation has beneficial effects on alpha asymmetry. Inconsistencies might have arisen since such trials relied on resting-state recordings, instead of active paradigms under challenge, as suggested by contemporary notions of alpha asymmetry.
We examined two groups of remitted, recurrently depressed females. In a “mindfulness support group”, EEG was recorded during neutral rest, and rest following a negative mood induction. Subsequently, participants received initial meditation instructions. EEG was then obtained during an active period of guided mindfulness meditation and rest following the active period. In a “rumination challenge group”, EEGwas obtained during the same resting conditions, whereas in the active period, initial meditation instructions were followed by a rumination challenge. A significant shift in mid-frontal asymmetry, yielding a pattern indicative of approach motivation, was observed in the mindfulness support group, specifically during the meditation period. This indicates that mindfulness meditation may have a transient beneficial effect, which enables patients to take an approach-related motivational stance, particularly under circumstances of risk.
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This paper is in an important area of research but there seemed to be a number of lacunae in the methodology as well as interpretation of results. Dr Jyothi discussed the findings and the various limitations of the study during her presentation.
Suwarna Chakraborty (PhD Scholar) presented the paper by Costa-Campos etal 2013 from Progress in Neuro-Psychopharmacology & Biological Psychiatry entitled "Interactive effects of N-acetylcysteine and antidepressants"
N-acetylcysteine (NAC), a glutathione precursor and glutamate modulator, has been shown to possess various clinically relevant psychopharmacological properties. Considering the role of glutamate and oxidative stress in depressive states, the poor effectiveness of antidepressant drugs (ADs) and the benefits of drug combination for treating depression, the aim of this study was to explore the possible benefit of NAC as an add on drug to treat major depression. For that matter we investigated the combination of subeffective and effective doses of NAC with subeffective and effective doses of several ADs in the mice tail suspension test.
The key finding of this study is that a subeffective dose of NAC reduced the minimum effective doses of imipramine and escitalopram, but not those of desipramine and bupropion. Moreover, the same subeffective dose of NAC increased the minimum effective dose of fluoxetine in the same model. In view of the advantages associated with using the lowest effective dose of antidepressant, the results of this study suggest the potential of a clinically useful interaction of NAC with imipramine and escitalopram. Further studies are necessary to better characterize the molecular basis of such interactions, as well as to typify the particular drug combinations that would optimize NAC as an alternative for treating depression.
Maltesh K (1st year PhD Scholar) presented the paper by Warden et al from Nature 2012 entitled: "A prefrontal cortex–brainstem neuronal projection that controls response to behavioural challenge"
The prefrontal cortex (PFC) is thought to participate in high-level control of the generation of behaviours (including the decision to execute actions); indeed, imaging and lesion studies in human beings have revealed that PFC dysfunction can lead to either impulsive states with increased tendency to initiate action, or to amotivational
states characterized by symptoms such as reduced activity, hopelessness and depressed mood. Considering the opposite valence of these two phenotypes as well as the broad complexity of other tasks attributed to PFC, we sought to elucidate the PFC circuitry that favours effortful behavioural responses to challenging situations. Here we develop and use a quantitative method for the continuous assessment and control of active response to a
behavioural challenge, synchronized with single-unit electrophysiology and optogenetics in freely moving rats. In recording from the medial PFC (mPFC), we observed that many neurons were not simply movement-related in their spike-firing patterns but instead were selectively modulated from moment to moment, according to the animal’s decision to act in a challenging situation. Surprisingly, we next found that direct activation of principal neurons in the mPFC had no detectable causal effect on this behaviour. We tested whether this behaviour could be causally mediated by only a subclass of mPFC cells defined by specific downstream wiring. Indeed, by leveraging optogenetic projection-targeting to control cells with specific efferent wiring patterns, we found that selective activation
of those mPFC cells projecting to the brainstem dorsal raphe nucleus (DRN), a serotonergic nucleus implicated in major depressive disorder, induced a profound, rapid and reversible effect on selection of the active behavioural state. These results may be of importance in understanding the neural circuitry underlying normal and pathological patterns of action selection and motivation in behaviour.
Dr Ghanshyam Pandey, Prof of Pharmacology from University of Illinois at Chicago gave a talk on "Neuroendocrine and Neuroimmune function in Depression and Suicide".
There are about 30,000 suicides per year in the US and is predominant among the young and geriatric (75+) populations. Suicide is a symptom rather than a disease and there are a number of risk factors such as depression, alcohol and drug abuse, early life trauma, family history, hopelessness, abnormal neurobiology, impulsive-aggressive behavior, conduct adjustment disorder, stress and contagion-copy cat cluster. The last few of these are predominantly seen in teenage populations which are also characterized by the fact that they are non-responsive to tricyclics but do respond to SSRIs.
Dr Pandey's group studied post mortem brain samples of depressed suicide victims and found that Protein and mRNA expression of Glucocorticoid receptors (GR) were lower in the prefrontal cortex(PFC) and amygdala. The same was true for Corticotropin Releasing Factor Receptor 1 (CRF-R1) and CRF Binding Proteins. Overall, dysregulation of the Hypothalamo-Pituitary-Adrenal (HPA) axis was seen to be related to altered expression of CRF and GR in PFC and amygdala. Interestingly, there was no change seen in the hippocampus. This could be because the sample population was young and perhaps the hippocampi had not yet been compromised.
In addition to the HPA axis, pro-inflammatory cytokines such as IL-1, IL-6, and INF-a were found to be increased and BDNF expression was decreased in depressed suicide victims.
Poojashree Mishra (2nd year PhD Scholar) presented the paper from Neuropsychopharmacology 2012 by Sun etal entitled "Gap Junction Dysfunction in the Prefrontal Cortex Induces Depressive-Like Behaviors in Rats".
Growing evidence has implicated glial anomalies in the pathophysiology of major depression disorder (MDD). Gap junctional communication is a main determinant of astrocytic function. However, it is unclear whether gap junction dysfunction is involved in MDD development. This study investigates changes in the function of astrocyte gap junction occurring in the rat prefrontal cortex (PFC) after chronic unpredictable stress (CUS), a rodent model of depression. Animals exposed to CUS and showing behavioral deficits in sucrose preference test (SPT) and novelty suppressed feeding test (NSFT) exhibited significant decreases in diffusion of gap junction channel permeable dye and expression of connexin 43 (Cx43), a major component of astrocyte gap junction, and abnormal gap junctional ultrastructure in the PFC. Furthermore, we analyzed the effects of typical antidepressants fluoxetine and duloxetine and glucocorticoid receptor (GR) antagonist mifepristone on CUS-induced gap junctional dysfunction and depressive-like behaviors. The cellular and behavioral alterations induced by CUS were reversed and/or blocked by treatment with typical antidepressants or mifepristone, indicating that the mechanism of their antidepressant action may involve the amelioration of gap junction dysfunction and the cellular changes may be related to GR activation. We then investigated the effects of pharmacological gap junction blockade in the PFC on depressive-like behaviors. The results demonstrate that carbenoxolone (CBX) infusions induced anhedonia in SPT, and anxiety in NSFT, and Cx43 mimetic peptides Gap27 and Gap26 also induced anhedonia, a core symptom of depression. Together, this study supports the hypothesis that gap junction dysfunction contributes to the pathophysiology of depression.
Neurogenesis in the Adult Brain: Implication for Treating Neuropsychiatric Disorders - Seminar by Neethi Prem
Neethi Prem (1st year PhD Scholar) presented her seminar on : Neurogenesis in the Adult Brain: Implication for Treating Neuropsychiatric Disorders.
Neethi explained the current understanding of neurogenesis in the Sub Granular Zone of DG and the Sub Ventricular Zone of lateral ventricles as well as the impact of neurotherapeutics on neurogenesis. Currently there is no consensus if neurogenesis plays a causal role or is an after-effect in the treatment of neuropsychiatric disorders through antidepressants or ECS.