Cross-species Comparison of Rodent and Human Decision-making in the Iowa Gambling Task in Select Neurological and Psychiatric Disorder: Translational Approach to Examine Age and Sex-specific Effect of Stress and Cortico-limbic Perturbations

Varsha Singh^1*Manjari Tripathi²SARAT P CHANDRA²Rohit Verma²Sushil K. Jha³Harvinder Singh Chhabra⁴Mrinmoy Chakrabarty⁵Shambhovi Mitra⁶Indupriya B.⁷Ankit Jha⁷Sakshi Sharma⁸Jyotsna Pandey⁸Divyanshi Pandey⁹Insha Shamshad⁹Ekta Ahlawat⁴Titli Saha⁸Chloe Cesar¹⁰Suman Jain²

• ¹Humanities and Social Science, Department of Humanities and Social Sciences, Indian Institute of Technology Delhi, New Delhi, India
• ²All India Institute of Medical Sciences, New Delhi, National Capital Territory of Delhi, India
• ³Jawaharlal Nehru University, New Delhi, National Capital Territory of Delhi, India
• ⁴Sri Balaji Action Medical Institute, A 4 Block, A 6 Block, Paschim Vihar, New Delhi, Delhi, 110063, India
• ⁵Indraprastha Institute of Information Technology Delhi, Delhi, India
• ⁶Indian Spinal Injuries Centre, New Delhi, National Capital Territory of Delhi, India
• ⁷University of Queensland – IIT Delhi Academy of Research (UQIDAR), Indian Institute of Technology, New Delhi, India
• ⁸School of Interdisciplinary Research, Indian Institute of Technology Delhi, New Delhi, NCT of Delhi, India
• ⁹Department of Humanities and Social Sciences, Indian Institute of Technology Delhi, New Delhi, Delhi, India
• ¹⁰Sorbonne Universités, Paris, France

Rodent models are widely used to understand cognitive changes in clinical disorders in humans. However, differences in the nervous system and in the environmental demands of the rodents and humans make it difficult to translate insights from animals to humans. Age and sex further impact brain health and increase vulnerability to disorders via exposure to care, nutrition, safety and enriched environment versus neglect, deprivation, threat and constraint environments. These differences impact on how we process information related to rewards and threats to make decisions. Though animal models allow investigations of precise brain regions critical for cognition such as the prefrontal cortex (PFC) and allow controlled exposure to stress disorder trajectories, the prefrontal cortex differs in size, cytoarchitecture, and anatomicalfunctional organization. Non-analogous structural-functional mapping of brain regions and cognitive deficits result in animal models of clinical conditions that poorly depict cognitive deficits experienced by humans, failing to causally link pathophysiology changes to clinical conditions and translate insights from animals to humans. We propose that the Iowa Gambling Task (IGT) is well characterized from molecules to behavior, but there is no rodent-human comparison of clinically diagnosed conditions marked with central nervous system perturbations specifically brain architecture and cognitive deficit in poor decision making. The IGT relies on intact cognitive, affective, and motivational systems in inhibitive control and cortico-limbic perturbations in humans and rodents could impact task in a comparable manner. A cross-species comparison accounting for sex and age was done on data pooled from human and rodent IGT studies (N = 892; human = 722; rodent = 170) to explore organism, sex and age-specific IGT decision making under tri-level stress: psychological stress, CNS and limbic perturbation. The key results showed adverse effect of stress, CNS perturbation and limbic perturbations; stress and CNS perturbations adversely affected human decision making; limbic perturbations showed age-specific effect in humans and sex-specific impairment in rodents. We observed preference for infrequent punishments was common in humans, females, and healthy group compared to rodents, males and CNS perturbed group. Findings provide insights for translational neuroscience involving rodent-human comparison of brain alteration and cognitive deficits for clinical and health neuroscience.