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irtuins mediate the sex differences in neurogenic response tohronic stress

. Sumana 1, K. Bhanu Chandra 1, Swati Maitra 1, B. Kiranmayee 1,nukriti Singh 1, Salil Saurav Pathak 2, Arvind Kumar 2, Sumanahakravarty 1,∗

Chemical Biology/Organic I Div., Indian Institute of Chemicalechnology, Tarnaka, Hyderabad 500007, IndiaCentre for Cellular and Molecular Biology, Habsiguda,yderabad 500007, India

-mail address: Sumana98@gmail.com (S. Chakravarty).Chronic stressful events affect brain reward and cognitive cir-

uitries and thus cause depression, anxiety and related moodisorders in human. Persistent adult neurogenesis in hippocam-al sub granular zone (SGZ), the neural substrate of the cognitiveircuitry, also gets affected in mood disorders. The molecularechanisms in chronic stress-induced mood disorders have been

nvestigated extensively in male rodents, despite the fact thathe prevalence rates for depressive disorders are twice as high inomen than men. Most of the studies in rodents suggest that male

ubjects are generally more resistant than female subjects to theffects of chronic stress and there might be gender differences inesponse of neural circuitries to stress. Recent research implicatespigenetic or chromatin regulatory mechanisms in neuroadaptivehanges in these circuitries which cause lasting changes in geneunctions. Our hypothesis is that sex hormones induce differentialpigenetic events in response to chronic stress in reward as well asognitive circuitries, resulting in sex difference in mood disorderhenotype.

We used adult male, female and overiectomized (OVX) BALB/cice to understand whether sex hormones play role in the differ-

ntial response of the brain circuitries to chronic stress. Mice werexposed to chronic unpredictable multiple stress (CUMS) paradigmor three weeks to induce mood disorders and molecular changesn striatal and hippocampal tissues were studied. CUMS inducedepression phenotype in all the stressed groups but with difference

n anxiety response.Sirt1 and 2, members of class III histone deacetylases (HDACs)

ere differentially regulated in both the circuitries in sex-specificay. Detail role played by both the histone deacetylases, and their

egulation by sex hormones are being investigated in detail. Howhese Sirtuins mediate the stress effects on neural and behaviouralesponses differentially, in both the sexes, are being explored.

oi:10.1016/j.ijdevneu.2012.03.268

nderstanding the role of synapses in the regulation of pre-ynaptic vesicle transport using the C. elegans model

hikha Ahlawat ∗, Kaushalya Murthy, Sandhya P. Koushika

National Centre for Biological Sciences, Tata Institute of Fundamentalesearch, Bangalore 560065, India

Neurons are composed of long, highly branched processes calledxons and synapses. Synapses are the major means through whicheurons communicate with their other cells (Ahmari et al., 2000a).ince major protein synthesis takes place in the cell body, theransport machinery has to be robust to carry cargo to and fromhe axon terminus. Major players of axonal transport are motorsanterograde and retrograde), adaptors, and tracks. The regula-ion of vesicle-mediated transport in nerve cells contributes the

evelopment and maintenance of synapse. Any defect in transportrocess can lead to development of major neurological disordersuch as Alzheimers disease. Synaptic vesicles and active zone pro-

uroscience 30 (2012) 640–671 653

tein precursors in neurons are delivered specifically to sites wheremature synapses form (Ahmari et al., 2000b). Although, evidenceexists in favor of regulation of synaptic protein delivery, but it ispoorly characterized. Thus it is important to investigate the mech-anisms of regulation of SV transport by the synapse.

To understand the role of synapses in regulation of directedtransport, we took approach of live imaging and genetics. Weobserved the flux (particles crossing in the vicinity of synapsesin both anterograde and retrograde direction) pattern of synapticvesicles in C. elegans in developmental stages.

Preliminary data shows signatures of directed transport in laterdevelopmental stages, suggesting possible role of mature synapsein directed transport. Synapse formation defective mutants studysuggests that synapse is required for the regulation of directedtransport. We observed that only anterograde transport is sensitiveto synapse, retrograde transport is insensitive. Anterograde fluxpattern indicates that synapse might be conveying the direction-ality signal through the anterograde motors. Thus far our resultssuggest that molecular motors play critical roles in regulation oftransport to synapses. Our ongoing experiments are attempting toprovide a mechanistic understanding of this phenomenon.

Reference

Ahmari, S.E., Buchanan, J., Smith, S.J., 2000a. Assembly of presynaptic active zonesfrom cytoplasmic transport packets. Nat. Neurosci. 3, 445–451.

Ahmari, S.E., Buchanan, J., Smith, S.J., 2000b. Assembly of presynaptic active zonesfrom cytoplasmic transport packets. Nat. Neurosci. 3 (May (5)), 445–451.

doi:10.1016/j.ijdevneu.2012.03.269

Sirtuins mediate depression associated neuroadaptations inbrain reward pathway

S.S. Pathak 1, S. Maitra 2, N. Khandelwal 1, S. Chakravarty 2, A.Kumar 1,∗

1 Epigenetics and Neuropsychiatry Lab., Centre for Cellular and Molec-ular Biology (CCMB), Uppal Road, Hyderabad, India2 Chemical Biology/Organic I Div., Indian Institute of Chemical Tech-nology (IICT), Tarnaka, Uppal Road, Hyderabad, India

E-mail address: akumar@ccmb.res.in (A. Kumar).The etiopathology of depression and related mood disorders in

adults is not well understood. Since these complex neuropsychi-atric disorders often get triggered by environmental stimuli suchas prolonged psychosocial stress, we hypothesize that epigeneticmechanisms might be involved in the etiopathology of mood dis-orders.

Nucleus accumbens (NAc, ventral striatum) and Caudate Puta-men (CP, dorsal striatum) are neural targets of the dopaminergicneurons of the mesolimbic dopamine reward pathway which orig-inates in the ventral tegmental area of the midbrain. This pathwayis associated with the rewarding effects of drugs of abuse, food, sex,etc., and is severely affected in depression. Depression and mooddisorder phenotype is reflected by the development of anhedoniaand various molecular and epigenetic events have recently beenimplicated in the mouse reward pathway. Sirtuins are class III his-tone deacetylases and have recently been shown to be involvedin diverse neuropathologies. In multicellular organisms, Sirtuinsdeacetylate histones and transcription factors and regulate stress,metabolism and other pathways. There are seven sirtuins in mam-mals with different function and subcellular localization. Recently it

has been shown that few of the sirtuins have roles in stress responseand neuroprotection.

We used social defeat mouse model for inducing depressionin C57bl/6 mice and mapped the changes in Sirt1 and 2 tran-