Speaker 4: Alan Frazer, USA

s | 3 15. Zhao YJ, Du MY, Huang XQ, Lui S, Chen ZQ, Liu J, Luo Y, Wang XL, Kemp GJ, & Gong QY (2014). Brain grey matter abnormalities in medication-free patients with major depressive disorder: a meta-analysis. Psychological Medicine, 44(14), 2927–2937 16. Qiu L, Huang X, Zhang J, Wang Y, Kuang W, Li J, Wang X, Wang L, Yang X, Lui S, Mechelli A, & Gong QY (2014). Characterization of major depressive disorder using a multiparametric classification approach based on high resolution structural images. Journal of Psychiatry & Neuroscience, 39(2), 78–86. 17. Du M, Liu J, Chen Z, Huang X, Li J, Kuang W, Yang Y, Zhang W, Zhou D, Bi F, Kendrick KM, & Gong QY (2014). Brain grey matter volume alterations in late-life depression. Journal of Psychiatry & Neuroscience, 39(6), 397–406. 18. Zhang H, Li L, Wu M, Chen Z, Hu X, Chen Y, Zhu H, Jia Z, & Gong Q (2015). Brain gray matter alterations in first episodes of depression: A meta-analysis of whole-brain studies. Neuroscience and Biobehavioral Reviews, 60:43–50. doi: 10.1016/j. neubiorev. 2015.10.011. 19. Chen Z, Zhang H, Jia Z, Zhong J, Huang X, Du M, Chen L, Kuang W, Sweeney JA, & Gong QY (2015). Magnetization transfer imaging of suicidal patients with major depressive disorder. Scientific Reports, 5, 9670. doi: 10.1038/srep09670. Speaker 3: Anthony Grace, USA Title: Imbalance between the amygdala and the hippocampus in down-modulating dopamine system responsivity in animal models of depression Abstract Dysregulation of the mesolimbic dopamine (DA) system has garnered increasing attention as a key component of major depressive disorder (MDD). It is thought to be particularly relevant to anhedonia, the reduced interest in pleasurable stimuli, which is considered to be a core symptom of MDD. We have shown that rats exposed to either Chronic Mild Stress (CMS) or Learned Helplessness, two stress-induced animal models of depression, resulted in stress-exposed animals showing a reduction in ventral tegmental area (VTA) DA neuron population activity, i.e. the number of DA neurons active and available to respond to environmentally salient rewarding stimuli. This suggests that in MDD, there is a reduced ability of the DA system to respond to rewarding stimuli, which could therefore represent the neural substrate of clinical anhedonia. Drawing from human neuroim-Dysregulation of the mesolimbic dopamine (DA) system has garnered increasing attention as a key component of major depressive disorder (MDD). It is thought to be particularly relevant to anhedonia, the reduced interest in pleasurable stimuli, which is considered to be a core symptom of MDD. We have shown that rats exposed to either Chronic Mild Stress (CMS) or Learned Helplessness, two stress-induced animal models of depression, resulted in stress-exposed animals showing a reduction in ventral tegmental area (VTA) DA neuron population activity, i.e. the number of DA neurons active and available to respond to environmentally salient rewarding stimuli. This suggests that in MDD, there is a reduced ability of the DA system to respond to rewarding stimuli, which could therefore represent the neural substrate of clinical anhedonia. Drawing from human neuroimaging research, we identified two candidate regions that were investigated in the present study. The infralimbic prefrontal cortex (ILPFC) is the rodent homologue of human Brodmann Area 25, a region that is established to be key to MDD pathophysiology and is under investigation as a target of deep brain stimulation for treatment resistant depression. We found that activation of the ILPFC or the habenula in normal rats potently suppressed VTA DA neuron population activity (p<0.05), albeit in different patterns. ILPFC activation primarily affected medial VTA DA neurons, whereas LHb activation inhibited more central and lateral VTA DA neurons. In rats that underwent CMS (which impacts primarily medial VTA DA neurons), only ILPFC inactivation restored VTA DA neuron population activity to normal levels, while LHb inactivation had no restorative effect on DA neuron population activity. We have also examined the impact of the rapid acting antidepressant ketamine. In rats exposed to learned helplessness, the decrease in DA neuron activity was accompanied by long-term depression in the hippocampus-accumbens circuit that normally activates the dopamine system, suggesting that the lack of hippocampal drive fails to offset the ILPFC down-regulation. A single dose of ketamine restores hippocampal-accumbens drive, normalizes dopamine neuron firing, and reverses behavioral despair in the forced swim test. These data suggest that the ILPFC and LHb regulate different subpopulations of DA neurons within the mesolimbic system. This appears to have important relevance to understanding the DA system deficits observed in the CMS model of MDD, as this striking pattern of differential regulation appears to explain the unique restorative capacity of ILPFC inactivation in reversing the abnormal DA system hypoactivity observed in this widely used model. Furthermore, these data highlight the importance of the ILPFC as a critical node in depressive circuitry and a potential link between affective and motivational systems in the rodent brain. Speaker 4: Alan Frazer, USA Title: Brain Circuits Involved in the AntidepressantLike Effects of Ketamine Alan Frazer, Ph.D.; Flavia Carreño, Ph.D.; Gregory Collins, Ph.D.; Daniel Lodge, Ph.D. Department of Pharmacology, University of Texas Health Science Center at San Antonio Abstract There is great interest in studying ketamine given the rapid and sustained behavioral improvement it causes in patients with treatment resistant depression. Much research has focused on the molecular mechanisms of action of ketamine and there is evidence that NMDA receptor antagonism is a necessary component of its activity. Further, such receptors on GABAergic interneurons in the hippocampus are likely to be a primary target for NMDA receptor antagonists.1 However, there is a lack of understanding with regard to the contribution of specific brain circuits involved in either its rapid and/or sustained antidepressant-like effects. We used different approaches to examine the role of the ventral hippocampus (vHipp)-medial prefrontal cortex (mPFC) pathway in ketamine’s sustained antidepressantlike response in rats, as measured by the use of the forced swim test (FST). These included (1) inactivating pharmacologically the vHipp to mPFC pathway with lidocaine; (2) determining if activation of the pathway using DREADDs would mimic the effect of ketamine in the FST; and (3) activating the pathway using optogenetics to see if this reproduced the effects of ketamineThere is great interest in studying ketamine given the rapid and sustained behavioral improvement it causes in patients with treatment resistant depression. Much research has focused on the molecular mechanisms of action of ketamine and there is evidence that NMDA receptor antagonism is a necessary component of its activity. Further, such receptors on GABAergic interneurons in the hippocampus are likely to be a primary target for NMDA receptor antagonists.1 However, there is a lack of understanding with regard to the contribution of specific brain circuits involved in either its rapid and/or sustained antidepressant-like effects. We used different approaches to examine the role of the ventral hippocampus (vHipp)-medial prefrontal cortex (mPFC) pathway in ketamine’s sustained antidepressantlike response in rats, as measured by the use of the forced swim test (FST). These included (1) inactivating pharmacologically the vHipp to mPFC pathway with lidocaine; (2) determining if activation of the pathway using DREADDs would mimic the effect of ketamine in the FST; and (3) activating the pathway using optogenetics to see if this reproduced the effects of ketamine or inactivating it optogenetically to determine if this prevented the effect of ketamine. All three approaches gave results from which it could be concluded that the vHipp to mPFC pathway is both necessary and sufficient for ketamine’s antidepressantlike effect. Activation or inhibition of other pathways neither reproduced ketamine’s effect nor blocked it.2 Because of this, we hypothesized that another way to mimic the antidepressant-like effect of ketamine would be to block or reduce GABAergic transmission in the hippocampus. L-655,708 is a negative allosteric modulator of GABAA receptors and as such, would be expected to block GABAergic activity. In addition, it exhibits selectivity for the α5 subunit of the GABAA receptor with this subunit being localized primarily in the hippocampus.3 Systemic administration of this drug produced a sustained (7 days) antidepressantlike effect in the FST. To examine possible rewarding effects of ketamine that could contribute to its abuse potential, selfadministration experiments were carried out. Ketamine was self-administered by rats. However, L-655,708 was not. It should be possible, then, to develop novel antidepressants that recapitulate the beneficial effects of ketamine without having abuse-liability. 4 | International Journal of Neuropsychopharmacology, 2016