Chronic stress induces activity, synaptic and transcriptional remodeling of the lateral habenula associated with deficits in motivated behaviors

Chronic stress is a major risk factor for the development of depression. In recent years, the lateral habenula (LHb) has emerged as a potential key structure in depression. LHb is connected with dopaminergic neurons in the ventral tegmental area (VTA) and serotoninergic neurons in the dorsal raphe nucleus (DR), and changes in these monoaminergic systems have been associated with depression-related behaviors. In my dissertation, I demonstrate that chronic stress-induced hyperactivity in LHb neurons projecting to VTA is associated with increased passive coping but not anxiety or anhedonia. Moreover, LHb→VTA neurons in mice with increased passive coping show increased burst and tonic firing as well as synaptic adaptations in excitatory inputs from the entopeduncular nucleus (EP). In vivo manipulations of EP→LHb or LHb→VTA neurons also selectively alter passive coping and effort-related motivation. Conversely, dorsal raphe (DR)-projecting LHb neurons do not show chronic stress-induced hyperactivity and are targeted indirectly by the EP. Using single-cell transcriptomics I reveal a set of genes that can collectively serve as biomarkers to identify mice with increased passive coping phenotype and differentiate LHb→VTA from LHb→DR neurons. Together, I provide a set of biological markers at the level of genes, synapses, cells and circuits that define a distinctive chronic stress-induced behavioral phenotype

Optogenetic Dissection of Entorhinal-Hippocampal Space Circuit

Spatial representation system of brain is comprised of place cells located in the hippocampus and grid cells, head-direction cells, and border cells found in the medial entorhinal cortex. There is a prominent circuitry between the hippocampus and the medial entorhinal cortex; however, exactly which entorhinal functional cell types project to hippocampus has not been determined yet. By injecting retrogradely transportable recombinant adeno-associated virus carrying channelrhodopsin-2 transgene in the hippocampus, optogenetic control over entorhinal neurons with direct projections to the hippocampus has been introduced. Using optogenetics together with electrophysiological recordings in vivo we were able to identify functionally defined hippocampus projecting entorhinal neurons as cell that responded with minimal latency to laser stimulations in the medial entorhinal cortex. A substantial portion of responsive cells were grid cells, but we also found other directionally or spatially modulated responsive cells, like head-direction and border cells, as well as principal unknown cells and interneurons. Our findings indicate that neural code transformation within the hippocampal-entorhinal circuit and generation of place fields may be achieved by combining broad spectrum of functionally defined inputs arising from medial entorhinal cortex

Chronic stress induces activity, synaptic and transcriptional remodeling of the lateral habenula associated with deficits in motivated behaviors

Chronic stress is a major risk factor for the development of depression. In recent years, the lateral habenula (LHb) has emerged as a potential key structure in depression. LHb is connected with dopaminergic neurons in the ventral tegmental area (VTA) and serotoninergic neurons in the dorsal raphe nucleus (DR), and changes in these monoaminergic systems have been associated with depression-related behaviors. In my dissertation, I demonstrate that chronic stress-induced hyperactivity in LHb neurons projecting to VTA is associated with increased passive coping but not anxiety or anhedonia. Moreover, LHb→VTA neurons in mice with increased passive coping show increased burst and tonic firing as well as synaptic adaptations in excitatory inputs from the entopeduncular nucleus (EP). In vivo manipulations of EP→LHb or LHb→VTA neurons also selectively alter passive coping and effort-related motivation. Conversely, dorsal raphe (DR)-projecting LHb neurons do not show chronic stress-induced hyperactivity and are targeted indirectly by the EP. Using single-cell transcriptomics I reveal a set of genes that can collectively serve as biomarkers to identify mice with increased passive coping phenotype and differentiate LHb→VTA from LHb→DR neurons. Together, I provide a set of biological markers at the level of genes, synapses, cells and circuits that define a distinctive chronic stress-induced behavioral phenotype

Pain modulates dopamine neurons via a spinal–parabrachial–mesencephalic circuit

Pain decreases the activity of many ventral tegmental area (VTA) dopamine (DA) neurons, yet the underlying neural circuitry connecting nociception and the DA system is not understood. Here we show that a subpopulation of lateral parabrachial (LPB) neurons is critical for relaying nociceptive signals from the spinal cord to the substantia nigra pars reticulata (SNR). SNR-projecting LPB neurons are activated by noxious stimuli and silencing them blocks pain responses in two different models of pain. LPB-targeted and nociception-recipient SNR neurons regulate VTA DA activity directly through feed-forward inhibition and indirectly by inhibiting a distinct subpopulation of VTA-projecting LPB neurons thereby reducing excitatory drive onto VTA DA neurons. Correspondingly, ablation of SNR-projecting LPB neurons is sufficient to reduce pain-mediated inhibition of DA release in vivo. The identification of a neural circuit conveying nociceptive input to DA neurons is critical to our understanding of how pain influences learning and behavior

Chronic Stress Induces Activity, Synaptic, and Transcriptional Remodeling of the Lateral Habenula Associated with Deficits in Motivated Behaviors

Chronic stress (CS) is a major risk factor for the development of depression. Here, we demonstrate that CS-induced hyperactivity in ventral tegmental area (VTA)-projecting lateral habenula (LHb) neurons is associated with increased passive coping (PC), but not anxiety or anhedonia. LHb→VTA neurons in mice with increased PC show increased burst and tonic firing as well as synaptic adaptations in excitatory inputs from the entopeduncular nucleus (EP). In vivo manipulations of EP→LHb or LHb→VTA neurons selectively alter PC and effort-related motivation. Conversely, dorsal raphe (DR)-projecting LHb neurons do not show CS-induced hyperactivity and are targeted indirectly by the EP. Using single-cell transcriptomics, we reveal a set of genes that can collectively serve as biomarkers to identify mice with increased PC and differentiate LHb→VTA from LHb→DR neurons. Together, we provide a set of biological markers at the level of genes, synapses, cells, and circuits that define a distinctive CS-induced behavioral phenotype