Marmoset emotional regulation during adolescence and adulthood, with a particular focus on risk-taking and the role of the subgenual anterior cingulate cortex in motivation and affective biases

Abstract

Adolescence is a critical period during animal development, characterised bywidespread neural and behavioural changes, including increases in exploratory behaviour and risk-taking. These behavioural and neurobiological changes are particularly evident in primates, where social groups and relationships are complex, and maturation of the prefrontal cortex (PFC) is prolonged, lasting from childhood into early adulthood. The PFC is responsible for a wide range of higher-order functions including decision-making, reward valuation, and social cognition. In humans, adolescence is the age range in which a significant proportion of psychiatric disorders first appear (Kessler et al., 2005), so it is theorised that adolescence may be a time during which individuals are particularly vulnerable to stressors that could interfere with the development of PFC subregions and produce psychiatric symptoms (Arnsten, 2004). A region of the PFC that has been highly correlated with psychiatric disorders, specifically mood disorders, is the subgenual anterior cingulate cortex (sgACC). Overactivation of sgACC in humans is observed in depression, and reducing neuronal activity in sgACC using deep brain stimulation alleviates depressive symptoms (Mayberg et al., 2005). However, the mechanisms underlying the functional development of PFC subregions like sgACC and behavioural changes during adolescence are not well understood, indicating a need for animal models. During my PhD, I have used the common marmoset (Callithrix jacchus) to investigate how exploratory behaviour changes during adolescence, as well as the role of sgACC in behaviours that are impaired in depression, specifically motivation in adolescents and adults and generation of positive affective biases in adults. My first experimental chapter uses adult marmosets to look at the role of sgACC in affective biases, specifically, if DREADDs-mediated sgACC overactivation impairs the animals’ ability to show a positive bias toward a stimulus associated with high value food reward. I developed a novel touchscreen-based task to assess affective bias in marmosets, in which during the week animals are trained to associate two stimuli with either a high or low food reward, and their response bias between the stimuli is assessed with a preference test at the end of the week. Both behavioural and cardiovascular data were analysed. There is a subtle behavioural effect of sgACC overactivation to reduce positive bias toward the highly rewarded stimulus, and overactivation also seems to blunt cardiovascular arousal to high value reward, such that the more blunted the cardiovascular arousal to high reward, the greater the reduction in positive bias at preference test. This project expands on previous work from the lab looking at the role of sgACC in appetitive arousal and anticipatory anhedonia, but looks specifically at behavioural output, which is particularly useful for understanding biological mechanisms of depression symptoms. My second and third experimental chapters investigate the effect of DREADDs-mediated overactivation of sgACC on motivation in adult and juvenile marmosets, the first such experiment to be conducted on juvenile animals in the lab. DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) are a cutting edge technique that allows for minimally-invasive brain manipulations via a single surgical infusion of viral vectors that induce long-term expression of either an excitatory or inhibitory DREADDs receptor into a brain region of interest. Previously in the lab, the role of sgACC in motivation in adult marmosets had been assessed with direct pharmacological overactivation using in-dwelling cannulae. My results corroborate these findings for DREADDs-mediated sgACC overactivation and identify changes in motivation across adolescence with DREADDs-mediated overactivation of sgACC. My fourth experimental chapter focuses on changes in marmoset exploratory behaviour from infancy to late adolescence, assessed using a novel object test. Novelty- and sensation-seeking can often be risky, and these behaviours are known to peak during human adolescence (Steinberg et al., 2017). Risk -taking has also been associated with negative mental health outcomes later in life (Smout et al., 2020). My work shows that risk-taking and novelty-seeking in marmosets also peaks during adolescence, indicating that these animals are a good model of human adolescent neurodevelopmental trajectories (Sawiak et al., 2018), but also of behavioural changes during adolescence.