Ongoing habenular activity is driven by forebrain networks and modulated by olfactory stimuli.

Ongoing neural activity, which represents internal brain states, is constantly modulated by the sensory information that is generated by the environment. In this study, we show that the habenular circuits act as a major brain hub integrating the structured ongoing activity of the limbic forebrain circuitry and the olfactory information. We demonstrate that ancestral homologs of amygdala and hippocampus in zebrafish forebrain are the major drivers of ongoing habenular activity. We also reveal that odor stimuli can modulate the activity of specific habenular neurons that are driven by this forebrain circuitry. Our results highlight a major role for the olfactory system in regulating the ongoing activity of the habenula and the forebrain, thereby altering brain's internal states.

Spontaneous activity governs olfactory representations in spatially organized habenular microcircuits.

The medial habenula relays information from the sensory areas via the interpeduncular nucleus to the periaqueductal gray that regulates animal behavior under stress conditions. Ablation of the dorsal habenula (dHb) in zebrafish, which is equivalent to the mammalian medial habenula, was shown to perturb experience-dependent fear. Therefore, understanding dHb function is important for understanding the neural basis of fear. In zebrafish, the dHb receives inputs from the mitral cells (MCs) of the olfactory bulb (OB), and odors can trigger distinct behaviors (e.g., feeding, courtship, alarm). However, it is unclear how the dHb processes olfactory information and how these computations relate to behavior. In this study, we demonstrate that the odor responses in the dHb are asymmetric and spatially organized despite the unorganized OB inputs. Moreover, we show that the spontaneous dHb activity is not random but structured into functionally and spatially organized clusters of neurons, which reflects the favored states of the dHb network. These dHb clusters are also preserved during odor stimulation and govern olfactory responses. Finally, we show that functional dHb clusters overlap with genetically defined dHb neurons, which regulate experience-dependent fear. Thus, we propose that the dHb is composed of functionally, spatially, and genetically distinct microcircuits that regulate different behavioral programs.

Evaluation of the role of nitric oxide in acid sensing ion channel mediated cell death.

Acid sensing ion channels (ASICs) are widely expressed in central and peripheral nervous system. They are involved in a variety of physiological and pathophysiological processes: synaptic transmission, learning and memory, pain perception, ischemia, etc. During ischemia, metabolic acidosis causes the drop of extracellular pH (pHe) which in turn activates ASICs. Activation of calcium permeable ASIC1a has been implicated in neuronal death. ASICs are modulated by several redox reagents, divalent cations and nitric oxide (NO). Although NO potentiates ASIC mediated currents, the physiological significance of such modulation has not been studied in detail. We have evaluated the role of endogenous NO in cell death at different pH, mediated by the activation of ASICs. At pH 6.1, death rates of ASIC1 expressing Neuro2A (N2A) cells are significantly higher in comparison to the cells that do not express ASICs. Amiloride, a blocker of ASICs protects the cell from acid-injury. Sodium nitroprusside, a potent NO donor not only increases the ASIC mediated currents but also increases cell death at low pH. L-Arg, the precursor of NO also potentiates ASICs in a pH dependent manner. L-Arg-induced NO production and potentiation of ASICs were observed at pHs 7.4, 7.2, 7.0 and 6.8. Lowering the pH below 6.8 did not result in significant production of NO or potentiation of ASICs upon L-Arg stimulation. Our results suggest that potentiation of ASICs by NO and subsequent cell death in vivo depends on the severity of acidosis. During mild and moderate acidosis, NO promotes cell death by potentiating ASICs, whereas this potentiation subsides in severe acidosis due to inhibition of NO synthase.