Periodic Reporting for period 1 - GONOGO (Multi-layered integration of motivated actions and their outcomes in basal ganglia circuits)
Reporting period: 2020-10-01 to 2022-09-30
We adapt our actions to situational demands and outcomes we desire. Motivated actions are driven by the valence of their outcome, which can be rewarding (positive valence) or aversive (negative valence), wherein we are inertly biased to actively pursue rewards and passively avoid aversive stimuli (Fig 1). This action bias is beneficial in many situations but makes it difficult to inhibit action in rewarding situations that require patience and initiate action to avoid aversive events. I aimed to study the neurobiological underpinnings of such valence-driven action selection in the basal ganglia (BG), a brain network consisting of two major pathways that are thought to govern action selection. Such action control is dysfunctional in patients with impulsivity disorders (e.g. behavioral or drug addictions) and depression, where action initiation for rewards is impulsive and action suppression is exaggerated under aversive conditions, respectively. Furthermore, as the proposal addresses a behavioral aspect that is often impaired in patients with psychiatric disorders, the results from this study will be useful in furthering research in psychiatric patients. Specifically, to translate clinical findings from studies in humans into relevant animal models and vice versa, I am engaged in a group project with several clinical psychiatrists, psychologists, and clinical researchers. The overall objective of this proposal was to identify causal mechanisms within the brain that underly action control using cutting-edge technology. This technology gives us a microscopic view of the brain that we can track the activity at the level of single neurons. Thereby, allowing us to understand how groups of neurons work together to achieve the intended behavior.
In the last 8 months, I successfully trained a sizeable cohort of rats (n = 10) in a novel behavioral task (described in the proposal) that addresses valence-driven action control. These rats were trained to perform a novel go/no-go task to study action selection under rewarding contingencies. In this task, rats are expected to withhold an action (no-go) or initiate an action (go) to either receive a reward (sucrose pellet). Although common in human studies, this is unprecedented in rodents. While the animals performed the task, neural data tracking the activity of hundreds of neurons simultaneously was measured. I measured activity from 2 major subregions of the medial prefrontal cortex (mPFC) in the brain - prelimbic (PL) and infralimbic (IL) cortices, namely. These mPFC subregions were chosen due to their strong connections to basal ganglia (BG), a brain network I intended to record from. The mPFC subregions are also hypothesized to play a dichotomous role in this action control - where PL plays a role in action initiation and IL plays a role in action suppression. Therefore, I hypothesized that the PL neurons played a role in encoding the "Go" trials and the IL neurons played a role in encoding "Nogo" trials. I found that the individual neurons in PL and IL did not encode Go and Nogo, respectively. Instead, PL and IL neurons showed subpopulations of neurons that encoded both Go and Nogo trials. However, the population or network activity amongst the PL or IL neurons exhibited a dichotomous role - where the PL population was better at encoding the Go trials and the IL population was better at encoding the Nogo trials.
Scientific advancement:
Current research does not address the neural mechanisms underlying the dichotomous role of mPFC in action control. So far, studies have only established the involvement of these mPFC regions in action control but how neurons within these subregions establish action control is not well understood. . Furthermore, the contribution of neuron-population activity in mPFC to action control has never been studied. I aim to achieve this using state-of-the-art technology (calcium imaging) and advanced data analysis of neural data (recorded using calcium imaging).
Socio-economic impact:
An important contributing factor to the impact of this project is the embedding of my research group in a larger clinical research team at the Amsterdam Medisch Centrum (AMC) Psychiatry department, where I will be involved in bi-weekly research and clinical meetings and monthly translational research meetings. The AMC accommodates several experts in relevant clinical disorders, such as drug addiction (Prof. v.d. Brink), obsessive-compulsive-disorder (OCD; Prof. Denys), autism spectrum disorders (Dr. Geurts), and depression (Prof. Bockting), all of which are pathologies that involve deficits in action control (i.e. the focus in this proposal). Apart from the research meetings, the Psychiatry department also organizes a mini-symposium once a year to bring together all relevant stakeholders (clinical and animal model researchers) to communicate their findings and facilitate translational research. I will be presenting the results from this project in this mini-symposium to share the results from this study with clinical researchers working on psychiatric disorders such as OCD and depression. Another factor is the Amsterdam Brain and Cognition Initiative (http://abc.uva.nl/(opens in new window)) where integration of my research with psychological and biological sciences is facilitated. Together, these close ties provide optimal conditions for me to set up translational, multidisciplinary research.
Current research does not address the neural mechanisms underlying the dichotomous role of mPFC in action control. So far, studies have only established the involvement of these mPFC regions in action control but how neurons within these subregions establish action control is not well understood. . Furthermore, the contribution of neuron-population activity in mPFC to action control has never been studied. I aim to achieve this using state-of-the-art technology (calcium imaging) and advanced data analysis of neural data (recorded using calcium imaging).
Socio-economic impact:
An important contributing factor to the impact of this project is the embedding of my research group in a larger clinical research team at the Amsterdam Medisch Centrum (AMC) Psychiatry department, where I will be involved in bi-weekly research and clinical meetings and monthly translational research meetings. The AMC accommodates several experts in relevant clinical disorders, such as drug addiction (Prof. v.d. Brink), obsessive-compulsive-disorder (OCD; Prof. Denys), autism spectrum disorders (Dr. Geurts), and depression (Prof. Bockting), all of which are pathologies that involve deficits in action control (i.e. the focus in this proposal). Apart from the research meetings, the Psychiatry department also organizes a mini-symposium once a year to bring together all relevant stakeholders (clinical and animal model researchers) to communicate their findings and facilitate translational research. I will be presenting the results from this project in this mini-symposium to share the results from this study with clinical researchers working on psychiatric disorders such as OCD and depression. Another factor is the Amsterdam Brain and Cognition Initiative (http://abc.uva.nl/(opens in new window)) where integration of my research with psychological and biological sciences is facilitated. Together, these close ties provide optimal conditions for me to set up translational, multidisciplinary research.