Vidyadhara DJ presented the work done so far on the MPTP mouse model of Parkinson's Disease.
Yarreiphang (PhD Scholar) presented the progress of his ongoing PhD research in the areas of Parkinson's Disease using an MPTP mice model.
Vidyadhara J (PhD Scholar) presented the progress of his ongoing PhD work in the area of Parkinson's Disease using an MPTP mice model.
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.
Sumitha (PhD Scholar) presented the paper by Valle et al., from Cell Death and Disease (2014) entitled "Tissue-specific deregulation of selected HDACs characterizes ALS progression in mouse models: pharmacological characterization of SIRT1 and SIRT2 pathways"
Acetylation homeostasis is thought to play a role in amyotrophic lateral sclerosis, and treatment with inhibitors of histone deacetylases has been considered a potential and attractive therapeutic approach, despite the lack of a thorough study of this class of proteins. In this study, we have considerably extended previous knowledge on the expression of 13 histone deacetylases in tissues (spinal cord and muscle) from mice carrying two different ALS-linked SOD1 mutations (G93A-SOD1 and G86R-SOD1). We have then focused on class III histone deacetylases SIRT1 and SIRT2 that are considered relevant in neurodegenerative diseases. SIRT1 decreases in the spinal cord, but increases in muscle during the progression of the disease, and a similar expression pattern is observed in the corresponding cell models (neuroblastoma and myoblasts). SIRT2 mRNA expression increases in the spinal cord in both G93A-SOD1 and G86R-SOD1 mice but protein expression is substantially unchanged in all the models examined. At variance with other sirtuin modulators (sirtinol, AGK2 and SRT1720), the well-known SIRT1 inhibitor Ex527 has positive effects on survival of neuronal cells expressing mutant SOD1, but this effect is neither mediated by SIRT1 inhibition nor by SIRT2 inhibition. These data call for caution in proposing sirtuin modulation as a target for treatment.
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.
Nesin Sibin (PhD Scholar) presented the paper by Zhao etal from the journal Stroke 2013 entitled "Constraint-Induced Movement Therapy Overcomes the Intrinsic Axonal Growth - Inhibitory Signals in Stroke Rats".
Background and Purpose —Constraint-induced movement therapy (CIMT) improves functional outcome in patients with stroke possibly through structural plasticity. We hypothesized that CIMT could enhance axonal growth by overcoming the intrinsic growth–inhibitory signals, leading eventually to improved behavioral performance in stroke rats.
Methods—Focal cerebral ischemia was induced by intracerebral injection of endothelin-1. Adult Wistar rats were divided into a sham-operated group, an ischemic group, and an ischemic group treated with CIMT. CIMT started at postoperative day 7 and continued for 3 weeks. Biotinylated dextran amine was injected into the contralateral sensorimotor cortex at postoperative day 14 to trace crossing axons at the cervical spinal cord. The expressions of Nogo-A, Nogo receptor, RhoA, and Rho-associated kinase in the peri-infarct cortex, and the expressions of biotinylated dextran amine, growth associated protein-43, synaptophysin, vGlut1, and postsynaptic density-95 in the denervated spinal cord were measured by immunohistochemistry and Western blots. Behavioral recovery was analyzed at postoperative days 29 to 32.
Results—Infarct volumes were not different between groups after stroke. CIMT significantly increased the length and the number of midline crossings of contralateral corticospinal axons to the denervated cervical spinal cord. CIMT significantly decreased the expressions of Nogo-A/Nogo receptor and RhoA/Rho-associated kinase in the peri-infarct cortex, and increased the expressions of growth associated protein-43, synaptophysin, vGlut1, and postsynaptic density-95 in the denervated cervical spinal cord. Behavioral performances assessed by the beam-walking test and the water maze test were improved significantly by CIMT.
Conclusions—CIMT promoted poststroke synaptic plasticity and axonal growth at least partially by overcoming the intrinsic growth–inhibitory signaling, leading to improved behavioral outcome.
Abhilash PL (PhD Scholar) presented the paper entitled "NADPH Oxidase and Aging Drive Microglial Activation, Oxidative Stress, and Dopaminergic Neurodegeneration Following Systemic LPS Administration" by Qin etal, from Glia 2013.
Parkinson’s disease is characterized by a progressive degeneration of substantia nigra (SN) dopaminergic neurons with age. We previously found that a single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) injection caused a slow progressive loss of tyrosine hydroxylase immunoreactive (THþIR) neurons in SN associated with increasing motor dysfunction. In this study, we investigated the role of NADPH oxidase (NOX) in inflammation-mediated SN neurotoxicity. A comparison of control (NOX2þ/þ) mice with NOX subunit gp91phox-deficient (NOX2/) mice 10 months after LPS administration (5 mg/kg, i.p.) resulted in a 39% (P < 0.01) loss of THþIR neurons in NOX2þ/þ mice, whereas NOX2/ mice did not show a significant decrease. Microglia (Iba1þIR) showed morphological activation in NOX2þ/þ mice, but not in NOX2/ mice at 1 hr.
Treatment of NOX2þ/þ mice with LPS resulted in a 12-fold increase in NOX2 mRNA in midbrain and 5.5–6.5-fold increases in NOX2 protein (þIR) in SN compared with the saline controls. Brain reactive oxygen species (ROS), determined using diphenyliodonium histochemistry, was increased by LPS in SN between 1 hr and 20 months. Diphenyliodonium (DPI), an NOX inhibitor, blocked LPS-induced activation of microglia and production of ROS, TNFa, IL-1b, and MCP-1. Although LPS increased microglial activation and ROS at all ages studied, saline control NOX2þ/þ mice showed age-related increases in microglial activation, NOX, and ROS levels at 12 and 22 months of
Together, these results suggest that NOX contributes to persistent microglial activation, ROS production, and dopaminergic neurodegeneration that persist and continue to increase with age.
Pooja Shri Mishra (PhD Scholar) presented the paper by Kang etal from Nature Neuroscience March 2013 entitled "Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis"
Oligodendrocytes associate with axons to establish myelin and provide metabolic support to neurons. In the spinal cord of amyotrophic lateral sclerosis (ALS) mice, oligodendrocytes downregulate transporters that transfer glycolytic substrates to neurons and oligodendrocyte progenitors (NG2+ cells) exhibit enhanced proliferation and differentiation, although the cause of these changes in oligodendroglia is unknown. We found extensive degeneration of gray matter oligodendrocytes in the spinal cord of SOD1 (G93A) ALS mice prior to disease onset.
Although new oligodendrocytes were formed, they failed to mature, resulting in progressive demyelination. Oligodendrocyte dysfunction was also prevalent in human ALS, as gray matter demyelination and reactive changes in NG2+ cells were observed in motor cortex and spinal cord of ALS patients. Selective removal of mutant SOD1 from oligodendroglia substantially delayed disease onset and prolonged survival in ALS mice, suggesting that ALS-linked genes enhance the vulnerability of motor neurons and accelerate disease by directly impairing the function of oligodendrocytes.
H Yarreiphang (Phd Scholar) presented the paper by Zheng etal from PLoS ONE Aug 2013 entitled "Autophagic Impairment Contributes to Systemic Inflammation-Induced Dopaminergic Neuron Loss in the Midbrain"
Background: Neuroinflammation plays an important role in the pathogenesis of Parkinson’s disease (PD), inducing and accelerating dopaminergic (DA) neuron loss. Autophagy, a critical mechanism for clearing misfolded or aggregated proteins such as a-synuclein (a-SYN), may affect DA neuron survival in the midbrain. However, whether autophagy contributes to neuroinflammation-induced toxicity in DA neurons remains unknown.
Results: Intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg) into young (3-month-old) and aged (16-month-old) male C57BL/6J mice was observed to cause persistent neuroinflammation that was associated with a delayed and progressive loss of DA neurons and accumulation of a-SYN in the midbrain. The autophagic substrate-p62 (SQSTM1) persistently increased, whereas LC3-II and HDAC6 exhibited early increases followed by a decline. In vitro studies further demonstrated that TNF-a induced cell death in PC12 cells. Moreover, a sublethal dose of TNF-a (50 ng/ml) increased the expression of LC3-II, p62, and a-SYN, implying that TNF-a triggered autophagic impairment in cells.
Conclusion: Neuroinflammation may cause autophagic impairment, which could in turn result in DA neuron degeneration in midbrain.