Sumitha Rajendra Rao (PhD Scholar) presented data from her ongoing PhD work on "Directed Differentiation of Human Embryonic Stem Cells".
Kumaresan UD (MPhil Scholar) presented the paper by Zhan et al in Nature Neuroscience entitled "Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior"
Microglia are phagocytic cells that infiltrate the brain during development and have a role in the elimination of synapses during brain maturation. Changes in microglial morphology and gene expression have been associated with neurodevelopmental disorders. However, it remains unknown whether these changes are a primary cause or a secondary consequence of neuronal deficits. Here we tested whether a primary deficit in microglia was sufficient to induce some autism-related behavioral and functional connectivity deficits. Mice lacking the chemokine receptor Cx3cr1 exhibit a transient reduction of microglia during the early postnatal period and a consequent deficit in synaptic pruning. We show that deficient synaptic pruning is associated with weak synaptic transmission, decreased functional brain connectivity, deficits in social interaction and increased repetitive-behavior phenotypes that have been previously associated with autism and other neurodevelopmental and neuropsychiatric disorders. These findings open the possibility that disruptions in microglia-mediated synaptic pruning could contribute to neurodevelopmental and neuropsychiatric disorders.
Kumari Anshu Jha (2nd year PhD scholar) presented her seminar on "Interneuron dysfunction in neuropsychiatric disorders". She focused on GABAergic dysfunction in Schizophrenia and Autism.
Anshu gave an overview of Interneuron functions (feedback & feedforward inhibition, network oscillations and synchrony, modulation of excitability, integration and cortical development and plasticity) and then highlighted the complexity of internuron types (classified based on morphological, molecular, electrophysiological properties - eg Markram 2004).
She then discussed the role of GABAergic neurons in the pathophysiology of Schizophrenia and then Autism from post-mortem studies and animal models (gene knockouts) while showing that GABA impairment seems to be present in a wide variety of neuropsychiatric disorders. She then went through the mechanisms through which these interneurons modulate network oscillations via electrical gap junctions and neurochemical modulations amongst the interneurons (for example Parvalbumin expressing basket cells impact gamma oscillations while somatostatin expressing interneurons impact beta oscillations).
Considering that the type of impairment is similar for schizophrenia and autism, the timing of the impairment seems to be a differentiator between these two disorders. Autism is seen in early childhood (diagnosed around 3 years of age when neuronal pruning is still ongoing) and the first onset of Schizophrenia happens in adolescence (when the neurons are fully formed but the myelination is still an ongoing process).
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.
Merlin (1st year MPhil Scholar) presented the paper by C. Salis et al. in Neurochemistry International, 2012 entitled "Iron and holotransferrin induce cAMP-dependent differentiation of Schwann cells"
The differentiation of myelin-forming Schwann cells (SC) is completed with the appearance of myelin proteins MBP and P(0) and a concomitant downregulation of markers GFAP and p75NTR, which are expressed by immature and adult non-myelin-forming SC. We have previously demonstrated that holotransferrin (hTf) can prevent SC dedifferentiation in culture (Salis et al., 2002), while apotransferrin (aTf) cannot. As a consequence, we used pure cultured SC and submitted them to serum deprivation in order to promote dedifferentiation and evaluate the prodifferentiating ability of ferric ammonium citrate (FAC) through the expression of MBP, P(0), p75NTR and c-myc. The levels of cAMP, CREB and p-CREB were also measured.
Results show that Fe(3+), either in its free form or as hTf, can prevent the dedifferentiation promoted by serum withdrawal. Both FAC and hTf were proven to promote differentiation, probably through the increase in cAMP levels and CREB phosphorylation, as well as levels of reactive oxygen species. This effect was inhibited by deferroxamine (Dfx, an iron chelator), H9 (a cAMP-PKA antagonist) and N-acetylcysteine (NAC, a powerful antioxidant).
Sumitha R (2nd year PhD scholar) presented her seminar on "Neuronal specification in spinal cord - Signals and Transcriptional codes".
She covered the role of BMP, Shh, Wnts, FGF and Retinoic acid in signaling and also how the concentration gradient of Class I (Pax, Dbx) and Class II genes (NKx family of transcription factors) determines whether a cell becomes a motor neuron or an interneuron.
Shilpa BM (3rd year PhD Scholar) presented her seminar of "Enriched Environment and recovery of Brain functions".
A number of studies suggest that enriched environments ameliorate the effects of traumatic brain injury; neurodevelopment and ageing; neurodegenerative diseases such as Alzheimers and Huntington's; depression, fear and stress; addictions; epilepsy... and seem to function via increase of cognitive reserve.
Benefits include increase in synaptic density, neurotrophic support, glial proliferation, neurogenesis, vasculature support. Several studies have been done in our labs (Subicular lesion studies by Anandh and Bindu B; Restraint stress by Ramkumar and Veena; Fear conditioning by Preethi; Depression by Mahati and now on Epilepsy as well).
Dr Rukmani (1st year MPhil Scholar) presented her seminar on "Role of Thyroid Hormones on Brain Development".
Hypothyroidism is considered to be the most common cause of mental retardation. Thyroid appears to mature by 12th week post conception. Iodine is used in synthesis of thyroid hormones and is a dietary requirement. Iodine deficiency during the first (and to some extent the second) trimester has serious consequences.
Most of T4 (thyroxine) is synthesized by thyroid and some T3 (triiodothyronine) as well. T4 and T3 crosses Blood Brain Barrier in Adults. In the developing brain, T4 passes more easily than T3 into the brain tissue. An increase in circulating T3 doesn't increase cerebral T3 in the developing brain. What gives these hormones much power is that they are able to delay gene transcription even though they don't stop it. For example, the Reelin gene that is necessary for ordered migration of developing cells across the cortical layers is regulated by thyroid hormones. In a normal cortex, the oldest neurons are in layer 6 while the newer ones traverse past to go to the layers above. In the Reeler cortex, the newest neurons fail to traverse older neurons in the lower layers and reach Layer II/III/IV/V. Interestingly, hypothyroidism is correlated with lesser myelination when the axonal diameters are less than a critical diameter.
Thyroid seems to affect neuronal migration, proliferation, the laminar effect, synaptogenesis, neuritogenesis... regulates bdnf and nt3.
Rukmani brought up an important point to note about comparing rodent and human studies. The rat model is very good for studying brain development as the sequence of events between rat and humans is similar, proportionate and comparable when we take onset of fetal thyroid action as a reference point. However, when we take birth as a reference point, we need to take into account that postnatal rat brain development is relatively more than human brain development.