Uma Ladiwala

Thyroid hormone regulates hippocampal neurogenesis in the adult rat brain

We have examined the influence of thyroid hormone on adult hippocampal neurogenesis, which encompasses the proliferation, survival and differentiation of dentate granule cell progenitors. Using bromodeoxyuridine (BrdU), we demonstrate that adult-onset hypothyroidism significantly decreases hippocampal neurogenesis. This decline is predominantly the consequence of a significant decrease in the survival and neuronal differentiation of BrdU-positive cells. Both the decreased survival and neuronal differentiation of hippocampal progenitors could be rescued by restored euthyroid status. Adult-onset hyperthyroidism did not influence hippocampal neurogenesis, suggesting that the effects of thyroid hormone may be optimally permissive at euthyroid levels. Our in vivo and in vitro results revealed that adult hippocampal progenitors express thyroid receptor isoforms. The in vitro studies demonstrate that adult hippocampal progenitors exhibit enhanced proliferation, survival and glial differentiation in response to thyroid hormone. These results support a role for thyroid hormone in the regulation of adult hippocampal neurogenesis and raise the possibility that altered neurogenesis may contribute to the cognitive and behavioral deficits associated with adult-onset hypothyroidism.

α2-adrenoceptor blockade accelerates the neurogenic, neurotrophic, and behavioral effects of chronic antidepressant treatment

Slow-onset adaptive changes that arise from sustained antidepressant treatment, such as enhanced adult hippocampal neurogenesis and increased trophic factor expression, play a key role in the behavioral effects of antidepressants. α2-Adrenoceptors contribute to the modulation of mood and are potential targets for the development of faster acting antidepressants. We investigated the influence of α2-adrenoceptors on adult hippocampal neurogenesis. Our results indicate that α2-adrenoceptor agonists, clonidine and guanabenz, decrease adult hippocampal neurogenesis through a selective effect on the proliferation, but not the survival or differentiation, of progenitors. These effects persist in dopamine β-hydroxylase knock-out (Dbh−/−) mice lacking norepinephrine, supporting a role for α2-heteroceptors on progenitor cells, rather than α2-autoreceptors on noradrenergic neurons that inhibit norepinephrine release. Adult hippocampal progenitors in vitro express all the α2-adrenoceptor subtypes, and decreased neurosphere frequency and BrdU incorporation indicate direct effects of α2-adrenoceptor stimulation on progenitors. Furthermore, coadministration of the α2-adrenoceptor antagonist yohimbine with the antidepressant imipramine significantly accelerates effects on hippocampal progenitor proliferation, the morphological maturation of newborn neurons, and the increase in expression of brain derived neurotrophic factor and vascular endothelial growth factor implicated in the neurogenic and behavioral effects of antidepressants. Finally, short-duration (7 d) yohimbine and imipramine treatment results in robust behavioral responses in the novelty suppressed feeding test, which normally requires 3 weeks of treatment with classical antidepressants. Our results demonstrate that α2-adrenoceptors, expressed by progenitor cells, decrease adult hippocampal neurogenesis, while their blockade speeds up antidepressant action, highlighting their importance as targets for faster acting antidepressants.

Recruitment of the Sonic hedgehog signalling cascade in electroconvulsive seizure-mediated regulation of adult rat hippocampal neurogenesis

Electroconvulsive seizure (ECS) induces structural remodelling in the adult mammalian brain, including an increase in adult hippocampal neurogenesis. The molecular mechanisms that underlie this increase in the proliferation of adult hippocampal progenitors are at present not well understood. We hypothesized that ECS may recruit the Sonic hedgehog (Shh) pathway to mediate its effects on adult hippocampal neurogenesis, as Shh is known to enhance the proliferation of neuronal progenitors and is expressed in the adult basal forebrain, a region that sends robust projections to the hippocampus. Here we demonstrate that the ECS‐induced increase in proliferation of adult hippocampal progenitors was completely blocked in animals treated with cyclopamine, a pharmacological inhibitor of Shh signalling. Our results suggest that both acute and chronic ECS enhance Shh signalling in the adult hippocampus, as we observed a robust upregulation of Patched (Ptc) mRNA, a component of the Shh receptor complex and a downstream transcriptional target of Shh signalling. This increase was rapid and restricted to the dentate gyrus, where the adult hippocampal progenitors reside. In addition, both acute and chronic ECS decreased Smoothened (Smo) mRNA, the other component of the Shh receptor complex, selectively within the dentate gyrus. However, ECS did not appear to influence Shh expression within the basal forebrain, the site from which it has been suggested to be anterogradely transported to the hippocampus. Together, our findings demonstrate that ECS regulates the Shh signalling cascade and indicate that the Shh pathway may be an important mechanism through which ECS enhances adult hippocampal neurogenesis.

Mechanisms of tissue injury in multiple sclerosis: opportunities for neuroprotective therapy

Development of neuroprotective therapies for multiple sclerosis is dependent on defining the precise mechanisms whereby immune effector cells and molecules are able to induce relatively selective injury of oligodendrocytes (OLs) and their myelin membranes. The selectivity of this injury could be conferred either by the properties of the effectors or the targets. The former would involve antigen specific recognition by either antibody or T cell receptor of the adaptive immune system. OLs are also susceptible to non antigen restricted injury mediated by components of the innate immune system including macrophages/microglia and NK cells. Target related selectivity could reflect the expression of death inducing surface receptors (such as Fas or TNFR-1) required for interaction with effector mediators and subsequent intracellular signaling pathways, including the caspase cascade. Development of therapeutic delivery systems, which would reach the site of disease activity within the CNS, will permit the administration of inhibitors either of the cell death pathway or of effector target interaction and opens new avenues to neuroprotection approach.

Probing differentiation in cancer cell lines by single-cell micro-Raman spectroscopy

Abstract. Single-cell micro-Raman spectroscopy has been applied to explore cell differentiation in single, live, and malignant cells from two tumor cell lines. The spectra of differentiated cells exhibit substantial enhancement primarily in the intensities of protein peaks with concomitant decrease in intensities of O─P─O asymmetric stretching peaks in DNA/RNA. Principal component analyses show that the spectral score of differentiated cells tends to asymptotically approach that of spectra obtained from normal neural stem cells/progenitors. This lends credence to the notion that the observed spectral changes are specific to differentiation, since upon differentiation, malignant cells become less malignant and tend toward benignity.

Superantigen presenting capacity of human astrocytes

We found that human fetal astrocytes (HFA) are able to support superantigen (SAG) staphylococcal enterotoxin B (SEB) and toxic shock syndrome toxin-1 (TSST-1)-induced activation of immediately ex vivo allogenic human CD4 T cells. Using radiolabelled toxins, we demonstrate that both SEB and TSST-1 bind with high affinity to MHC class II antigen expressing astrocytes; binding is displaceable with excess cold toxin. Competition experiments further indicate that TSST-1 and SEB at least partially compete with each other for binding to astrocytes suggesting they bind to the same HLA-DR region on these cells. Our study supports the hypothesis that SAG would be capable of stimulating immune responses within the human CNS and contribute to persistence or recurrence of inflammatory responses within this compartment.

A diffusion based study of population dynamics: Prehistoric migrations into South Asia

A diffusion equation has been used to study migration of early humans into the South Asian subcontinent. The diffusion equation is tempered by a set of parameters that account for geographical features like proximity to water resources, altitude, and flatness of land. The ensuing diffusion of populations is followed in time-dependent computer simulations carried out over a period of 10,000 YBP. The geographical parameters are determined from readily-available satellite data. The results of our computer simulations are compared to recent genetic data so as to better correlate the migratory patterns of various populations; they suggest that the initial populations started to coalesce around 4,000 YBP before the commencement of a period of relative geographical isolation of each population group. The period during which coalescence of populations occurred appears consistent with the established timeline associated with the Harappan civilization and also, with genetic admixing that recent genetic mapping data reveal. Our results may contribute to providing a timeline for the movement of prehistoric people. Most significantly, our results appear to suggest that the Ancestral Austro-Asiatic population entered the subcontinent through an easterly direction, potentially resolving a hitherto-contentious issue.