Periodic Reporting for period 1 - CoMPOSE (Cortical Microcircuits: Parvalbumin neurons Orchestrate Stress Eating)
Periodo di rendicontazione: 2020-06-01 al 2022-05-31
Stress leads to enhanced food intake and a shift in dietary choices towards more high-caloric and unhealthy food. While this serves an adaptive purpose to replenish energy stores after a physical challenge, in modern society where continuous psychological stressors are present and cheap unhealthy food easily accessible, this likely contributes to tthe current alarming situation regarding obesity levels, with severe consequences for our health. Moreover, people with an eating disorder, like binge-eating disorder, are vulnerable to the effects of stress on maintaining their pathology. What circuits are implicated in these disorders is poorly understood. Human and animal studies both point to a critical role of the prefrontal cortex in coordinating stress-induced food intake. The prefrontal cortex is a highly heterogenous structure sending coordinated neuronal output to many brain regions with opposing roles in food regulation. This indicates that these circuits are under tight regulation of local interneurons. However, how interneurons coordinate circuits for stress-induced feeding behaviour and which projection neurons in the prefrontal cortex are important for stress-eating, is not known. To investigate this, we use a mouse model with stress leading to enhanced intake of palatable food. In this project I use this model to understand how inhibitory interneurons shape output patterns of prefrontal cortical pyramidal neurons in a projection-specific manner to drive stress-induced food intake. We focus on communication between the cortex and the hypothalamus (a region with a prominent role in regulating food intake) This study yields important insight into the circuit mechanisms underlying stress effects on food intake. Studying how this phenomenon arises at the level of neuronal circuits may ultimately provide evidence-based targets for prevention strategies.
By making activity of prefrontal cortex neurons that communicate with the hypothalamus sensitive to light (i.e. ‘optogenetics’) we studied the role of this pathway in food intake. Interestingly, depending on the rhythm of stimulation we observed either decreases or increases in food intake. Moreover, it specifically enhanced palatable food but not chow intake and increases the frequency of meal initiation when animals are in a more sated state. We assessed whether stimulating the cortical-hypothalamic pathway was in itself pleasant or unpleasant, using a place preference paradigm, but we found no net effect, indicating that the food intake changes occur against an unchanging emotional background. Together, these data suggests that this pathway can drive hedonic feeding an important driving mechanism of stress-eating.
To establish under which conditions cortical neurons projecting to the hypothalamus are necessary for food intake we used opto- and chemogenetic inhibition experiments. Closed-loop optogenetic inhibition of these neurons when mice are close to food did not affect their intake. In addition, a more chronic form of inhibition using chemogenetics also did not yield a significant effect on food intake. However, preliminary data shows that these neurons might become engaged in regulating food intake after social stress. We then used in vivo electrophysiology to record from different cell types (putative interneurons and pyramidal neurons) within the prefrontal cortex to show that prefrontal cortex neurons do not respond strongly to food interactions under normal conditions. To investigate whether these neurons become more engaged after stress we use a social stress model which is known to increase intake of palatable food. Exposure to the social stressor itself highly impacts the firing rate of prefrontal cortical neurons over long-time scales. In addition, we have established recordings of identified neurons in the prefrontal cortex that communicate with the hypothalamus to investigate their role in stress and stress-eating.
Together these results make an important step in identifying how prefrontal cortical neuronal ensembles govern stress-eating behaviours.
To establish under which conditions cortical neurons projecting to the hypothalamus are necessary for food intake we used opto- and chemogenetic inhibition experiments. Closed-loop optogenetic inhibition of these neurons when mice are close to food did not affect their intake. In addition, a more chronic form of inhibition using chemogenetics also did not yield a significant effect on food intake. However, preliminary data shows that these neurons might become engaged in regulating food intake after social stress. We then used in vivo electrophysiology to record from different cell types (putative interneurons and pyramidal neurons) within the prefrontal cortex to show that prefrontal cortex neurons do not respond strongly to food interactions under normal conditions. To investigate whether these neurons become more engaged after stress we use a social stress model which is known to increase intake of palatable food. Exposure to the social stressor itself highly impacts the firing rate of prefrontal cortical neurons over long-time scales. In addition, we have established recordings of identified neurons in the prefrontal cortex that communicate with the hypothalamus to investigate their role in stress and stress-eating.
Together these results make an important step in identifying how prefrontal cortical neuronal ensembles govern stress-eating behaviours.
The current project has laid the foundation for further investigation on how cortical and hypothalamic systems communicate with each other to shape feeding behavior under normal and under stressed circumstances. Typically these systems were instead studied by themselves (rather than investigating their cross-talk) and not often in the context of stressed internal states.
Beyond the scientific impact, this work can ultimately contribute to the development of evidence-based treatment strategies for invidiuals that overconsume food. Notably, there are currently ongoing developments in terms of non-invasive neuromodulation in humans (e.g. Transcranial magnetic stimulation (TMS)). These approaches can alter activity of the prefrontal cortex in humans. Different stimulation parameter settings inducing distinct effects in the human prefrontal cortex. As mentioned, stress-driven food intake can have serious consequences in individuals prone to develop obesity or in those with eating disorders characterized by binge eating. To better understand what kind of TMS procedures might be beneficial in the context of such diseases, it is relevant to better understand the neurobiological principles by which the PFC shapes food intake behavior. The current work can make a contribution to understanding these important principles.
Beyond the scientific impact, this work can ultimately contribute to the development of evidence-based treatment strategies for invidiuals that overconsume food. Notably, there are currently ongoing developments in terms of non-invasive neuromodulation in humans (e.g. Transcranial magnetic stimulation (TMS)). These approaches can alter activity of the prefrontal cortex in humans. Different stimulation parameter settings inducing distinct effects in the human prefrontal cortex. As mentioned, stress-driven food intake can have serious consequences in individuals prone to develop obesity or in those with eating disorders characterized by binge eating. To better understand what kind of TMS procedures might be beneficial in the context of such diseases, it is relevant to better understand the neurobiological principles by which the PFC shapes food intake behavior. The current work can make a contribution to understanding these important principles.