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.
Maltesh Esatlam (PhD Scholar) presented the paper by Rosas-Vidal LE et al from Neuropsychopharmacology 2014 entitled "Hippocampal-Prefrontal BDNF and Memory for Fear Extinction".
Infusing brain-derived neurotrophic factor (BDNF) into the infralimbic (IL) prefrontal cortex is capable of inducing extinction. Little is known, however, about the circuits mediating BDNF effects on extinction or the extent to which extinction requires BDNF in IL. Using local pharmacological infusion of BDNF protein, or an antibody against BDNF, we found that BDNF in the IL, but not prelimbic (PL) prefrontal cortex, is both necessary and sufficient for fear extinction. Furthermore, we report that BDNF in IL can induce extinction of older fear memories (14 days) as well as recent fear memories (1 day). Using immunocytochemistry, we show that BDNF is increased in the ventral hippocampus (vHPC), but not IL or PL, following extinction training. Finally, we observed that infusing BDNF into the vHPC increased the firing rate of IL, but not PL neurons in fear conditioned rats. These findings indicate that an extinction-induced increase in BDNF within the vHPC enhances excitability in IL targets, thereby supporting extinction memories.
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.
Kumari Anshu (2nd year PhD scholar) presented the paper by Giovanoli etal from the journal Science issue of 1st March 2013 entitled "Stress in Puberty Unmasks Latent Neuropathological Consequences of Prenatal Immune Activation in Mice".
Prenatal infection and exposure to traumatizing experiences during peripuberty have each been associated with increased risk for neuropsychiatric disorders. Evidence is lacking for the cumulative impact of such prenatal and postnatal environmental challenges on brain functions and vulnerability to psychiatric disease. Here, we show in a translational mouse model that combined exposure to prenatal immune challenge and peripubertal stress induces synergistic pathological effects on adult behavioral functions and neurochemistry. We further demonstrate that the
prenatal insult markedly increases the vulnerability of the pubescent offspring to brain immune changes in response to stress. Our findings reveal interactions between two adverse environmental factors that have individually been associated with neuropsychiatric disease and support theories that mental illnesses with delayed onsets involve multiple environmental hits.
Sunil Tripathi (2nd year PhD Scholar) presented the paper by Hartmann etal in Neuropharmacology 2012 entitled "The involvement of FK506-binding protein 51 (FKBP5) in the behavioral and neuroendocrine effects of chronic social defeat stress"
Chronic stress is increasingly considered to be a main risk factor for the development of a variety of psychiatric diseases such as depression. This is further supported by an impaired negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, which has been observed in the majority of depressed patients. The effects of glucocorticoids, the main hormonal endpoint of the HPA axis, are mediated via the glucocorticoid receptor (GR) and the mineralocorticoid receptor. The FK506-binding protein 51 (FKBP5), a co-chaperone of the Hsp90 and component of the chaperone-receptor heterocomplex, has been shown to reduce ligand sensitivity of the GR. This study aimed to investigate the function of FKBP5 as a possible mediator of the stress response system and its potential role in the development of stress related diseases. Therefore, we assessed whether mice lacking the gene encoding FKBP5 (51KO mice) were less vulnerable to the adverse effects of three weeks of chronic social defeat stress. Mice were
subsequently analyzed with regards to physiological, neuroendocrine, behavioral and mRNA expression alterations. Our results show a less vulnerable phenotype of 51KO mice with respect to physiological and neuroendocrine parameters compared to wild-type animals. 51KO mice demonstrated lower adrenal weights and basal corticosterone levels, a diminished response to a novel acute stimulus and an enhanced recovery, as well as more active stress-coping behavior. These results suggest an enhanced negative glucocorticoid feedback within the HPA axis of 51KO mice, possibly modulated by an increased sensitivity of the GR.
Shruti S (2nd year PhD scholar) presented the paper "Treatment with a coinducer of the heat shock response delays muscle denervation in the SOD1-G93A mouse model of amyotrophic lateral sclerosis" by Bernadett Kalmar, Emem Edet-Amana & Linda Greensmith from the journal Amyotrophic Lateral Sclerosis, 2012.
We undertook a longitudinal study of the histological and biochemical changes at the neuromuscular junction (NMJ)
in muscles of SOD1-G93A mice. We also assessed these functions in mice treated with a known heat shock protein
inducer, arimoclomol. Tissue samples of treated and untreated mSOD mice were analysed for AChE and ChAT enzyme activities as markers of neuromuscular function. Sections of hindlimb muscles (TA, EDL and soleus) were also stained for succinate dehydrogenase and silver cholinesterase activities as well as for immunohistochemistry.
Hsp70 levels were also measured from muscle samples using ELISA. Results showed that denervation and nerve sprouting were present at symptom onset in fast muscles, although slow muscles remained fully innervated. Cholinergic enzyme activities were reduced prior to denervation and declined further with disease progression. Reduction of endplate size, a slow to fast shift in muscle phenotype was also observed. Treatment with arimoclomol delayed the appearance of these changes, increased innervation, cholinergic enzyme activities and endplate size and reversed muscle fi bre transformation. These beneficial effects of arimoclomol in muscles were accompanied by an increase in Hsp70 expression.
In conclusion, our results indicate that pharmacological targeting of muscles at early stages of disease may be a successful strategy to ameliorate disease progression in ALS.
Vijaya Kumar (2nd year MPhil scholar) presented the paper "Corticosterone synthesis inhibitor metyrapone ameliorates chronic hypobaric hypoxia induced memory impairment in rat" by Iswar Baitharu etal in Behavioural Brain Research (2012).
Chronic exposure to hypobaric hypoxia causes oxidative stress and neurodegeneration leading to memory impairment. The present study aimed at investigating the role of corticosterone in hypoxia induced neurodegeneration and effect of metyrapone, a corticosterone synthesis inhibitor that reduces the stress induced elevation of corticosterone without affecting the basal level, in ameliorating chronic hypobaric hypoxia induced cognitive decline.
Rats were exposed to simulated altitude of 25,000 ft for 0, 3, 7, 14 and 21 days to determine the temporal alterations in corticosterone and its receptors following exposure to hypobaric hypoxia. Our results showed an elevation of corticosterone in plasma and hippocampal tissue following 7 days of exposure, which declined on prolonged hypoxic exposure for 21 days. A concomitant increase in ROS and lipid peroxidation was observed along with depletion of intracellular antioxidants. Glucocorticoid and mineralocorticoid receptors were upregulated on 3 and 7 days of hypoxic exposure. Though expression of Glut1 and Glut3 were upregulated on 3 days of hypoxic exposure, sharp decline in Glut1 expression following 7 days of hypoxic exposure leads to reduced neuronal glucose uptake.
Administration of metyrapone from 3rd to 7th day of hypoxic exposure to suppress hypoxia induced increase in corticosterone levels resulted in reduced oxidative damage, neurodegeneration and improvement of intracellular energy status. The metyrapone treated hypoxic animals performed better in the Morris Water Maze.
Further, administration of exogenous corticosterone along with metyrapone during hypoxic exposure blunted the neuroprotective effect of metyrapone indicating a role for corticosterone in mediating hypobaric hypoxia induced neurodegeneration and memory impairment.
Debasish Majumder (2nd year MPhil Scholar) presented a paper by Michael Lukas and Inga D. Neumann in Neuropharmacology 62 (2012) entitled "Nasal application of neuropeptide S reduces anxiety and prolongs memory in rats: Social versus non-social effects".
Recent studies demonstrated potent behavioral effects of centrally applied neuropeptide S (NPS) in mice and rats. These include increased arousal and wakefulness, facilitation of fear extinction and object memory consolidation and anxiolysis. Here, we compared the effects of NPS on both social and nonsocial memory, in male rats, and on social preference/social anxiety versus non-social anxiety after either intracerebroventricular (icv) or nasal application. Intranasal application of neuropeptides has been successfully employed to alter behavioral parameters in humans and rodents, but studies concerning nasal application of NPS are lacking so far.
First, we confirmed the facilitatory effect of icv NPS (1 nmol) on object discrimination after an inter-exposure interval (IEI) of 240 min. These effects were context dependent, as icv NPS (1 nmol) did not prolong social memory in a social discrimination paradigm.
Second, we confirmed the anxiolytic effect of icv NPS (1 nmol) on the elevated plus-maze, whereas neither icv NPS (1 nmol) nor NPS receptor antagonist (10 nmol) altered social preference/social avoidance behavior. Third, nasal NPS (4e40 nmol applied topically on the rhinarium) facilitated object discrimination in a dose-dependent manner. Also, the anxiolytic effect of NPS on the elevated plus-maze could be confirmed after nasal administration (40 nmol). In contrast, identical doses of subcutaneously injected NPS failed to produce corresponding behavioral effects in both tests.
Our findings provide evidence for memory-enhancing and anxiolytic effects of icv NPS in a non-social context. We could further show that these effects are context-specific, as social memory and social preference behavior remained unchanged after icv NPS. The effects of icv NPS were replicated by nasal application of the neuropeptide. Thus, nasal application of NPS seems to be a useful method in rodents for screening for behavioral or physiological effects before more specific and time-consuming, intracerebral methods are employed, and may represent a viable therapeutic approach for NPS treatment ofpatients with psychiatric illnesses such as anxiety or panic disorders.
Anu Mary Varghese (3rd year PhD Scholar) presented her journal club on the paper "Treatment with trichostatin A initiated after disease onset delays disease progression and increases survival in a mouse model of amyotrophic lateral sclerosis" by Young-Eun Yoo, Chien-Ping Ko in Experimental Neurology, June 2011.
Recent studies suggest that progressive motoneuron death in amyotrophic lateral sclerosis (ALS) is non-cell
autonomous and may involve the participation of non-neuronal cells such as glial cells and skeletal muscle.
Therefore, a drug that targets motoneurons as well as neighboring non-neuronal cells might be a potential
therapeutic strategy to delay disease progression in ALS. Trichostatin A (TSA), a histone deacetylase (HDAC)
inhibitor, has shown protective effects in multiple cell types implicated in ALS by resetting gene transcription
proﬁles through increased histone acetylation. To test whether TSA could serve as a potential therapeutic
agent, we intraperitoneally injected TSA from postnatal day 90 (P90), after disease symptoms appear, until
P120 or the end-stage in SOD1-G93A mice. We found that TSA ameliorated motoneuron death and axonal
degeneratio n in SOD1-G93A mice. Reduced gliosis and upregulation of the glutama te transporter (GLT-1)
were also observed in the spinal cord of TSA-treated SOD1-G93A mice. In addition, TSA ameliorated muscle
atrophy and neuromuscular junction (NMJ) denervation, which are the pathological characteristics of ALS
found in skeletal muscle. Improved morphology in TSA-treated SOD1-G93A mice was accompanied by
enhanced motor functions as assessed by rota-rod and grip strength analyses. Furthermore, TSA treatment
signiﬁcantly increased the mean survival duration after the treatment by 18% and prolonged lifespan by
7%. Our ﬁndings suggest that TSA may provide a potential therapy to slow disease progres sion as well as to enhance motor performance to improve the quality of life for ALS patients.
One of the major critiques was that the paper did not consider the side effects of the drug as it has broad spectrum effects that could have serious consequences - for example it is likely to be carcinogenic.