“Starter Cells” Mediate Stress-Induced Depression-Like Behaviors
Post by Amanda Engstrom
The takeaway
In this study, researchers identified a small population of stress-responsive neurons, termed “starter cells”, in subregions of the hypothalamus-habenula circuit. These neurons are required for the development of depression-like behaviors in mice.
What's the science?
Chronic stress has long been considered a major risk factor for depression. Identifying specific neurons that respond to stress could offer insights into anti-depressant interventions. Experience-responsive neuronal ensembles are small populations of neurons that are functionally involved in distinct experiences. The lateral habenula (LHb) and the lateral hypothalamus (LH), which projects into the LHb, have been implicated in encoding aversion and depression-like behaviors during chronic stress. However, the core stress-responsive neurons within this circuit have not been identified. This week in Neuron, Zheng and colleagues identified a small population of neurons within the LH-LHb circuit, investigating their role in mediating depression-like behaviors due to stress.
How did they do it?
The authors combined c-fos immunostaining (a marker for neuronal activity) and a Robust Activity Marking (RAM) system to identify the functional neurons within the LH-LHb circuit that respond to stress. RAM is a viral strategy to capture and label experience-responsive neurons in mice. Using this approach, the mice were exposed to various types of stress, such as restraint stress, and the authors determined which cells were activated in response to stress. They then used a chemogenetic strategy where they expressed a compound to inhibit the identified neurons while the mice were exposed to stress. This enabled them to determine the effect on depression-like behaviors when these neurons were nonfunctional. In a complementary experiment, the authors used photostimulation, which uses light to activate these same cells to mimic the activity of the neurons in the absence of a stressor and determine if the mice would display depressive-like behaviors. To characterize the synaptic connections from the LH stress-responsive neurons to LHb subpopulations the authors used optogenetics - assisted electrophysiology, a technique that uses optical and genetic manipulation to control neuronal activity while simultaneously recording electrical activity. Finally, they visualized the process of neuronal recruitment by labeling stress-responsive LHb neurons via RAM at different stages of chronic stress.
What did they find?
After exposing mice to stress the authors identified a small population of neurons in the LHb and the LH (10% and 5% respectively) that were activated and labeled via the RAM system as well as c-fos positive. In both the LH and the LHb the active cells localized to subregions, specifically the middle part of the lateral hypothalamus (mLH) and the medial part of the lateral habenula (LHbM). Chemogenetic inhibition of the stress-responsive mLH or the LHbM neurons during chronic stress stopped the development of depression-like behaviors in mice. Additionally, activating these neurons via photostimulation is sufficient to cause depression-like behaviors. These data suggest that both regions are required for the development of depression-like behaviors caused by chronic stress. Using optogenetics-assisted electrophysiology, the authors showed that the stress-responsive neurons in the mLH and LHbM formed dominant excitatory connections after one exposure to stress, and they are selectively potentiated during chronic stress. The authors termed these cells “starter cells”. LHbM starter cells propagate hyperactivity across the entire LHb via local excitatory connections. Finally, the authors visualized the progressive recruitment of LHb neurons over time due to chronic stress. Initially, very little fluorescence signified very few stress-induced neurons, but they gradually increased over time. This indicates that initially stress-irresponsive LHb neurons were gradually becoming responsive, and the intensity of this response increased over time. The LHb stress-responsive neurons were initially limited to the LHbM and gradually spread throughout the entire LHb.
What's the impact?
This study identified a small population of stress-responsive neurons in subregions of the lateral hypothalamus (LH) and LH lateral habenula (LHb) that are critical for stress-induced depression-like behavior in mice. The authors identified and characterized a novel core functional unit within the larger LH-LHb circuit, further highlighting the importance of ensemble sparsity (a small number of functional cells within a larger ensemble) in various brain functions. Moreover, by identifying stress-responsive neurons, these data offer new insights into potential targets for antidepressant therapies.
