Learning and relearning deficits in a mouse model of depression

Major depressive disorder (MDD) is among the most prevalent psychiatric conditions worldwide [1]. Beyond its emotional and physiological impact, MDD is frequently characterized by cognitive disturbances [2]. Although treatments exist, 30% of patients remain resistant to conventional antidepressant treatment. Moreover, among patients who respond to treatment, 50% eventually relapse. Now the cognitive symptoms associated with depression are not only highly resistant to conventional pharmacotherapy [3] but may also contribute significantly to the broader phenomenon of treatment resistance [4]. Among these cognitive disturbances, we hypothesized that stress, a known predisposing factor for depression, may drive deficits in memory encoding (learning) and/or updating (cognitive inflexibility or relearning). To validate this hypothesis, we first compared in an initial cohort of mice, emotional state and learning abilities of mice after either 28 days of chronic corticosterone (CORT) supplementation in drinking water to mimic chronic exposure to stress or 28 days of the corresponding solvent [5]. Decision-making was assessed in a separate cohort through a probabilistic reinforcement discrimination (PRD) task. In this task, animals were presented with two wheels that could be turned clockwise or counter-clockwise to receive a condensed milk reward. To maximize reinforcement, they had to discriminate the high-probability option (rewarded 75% of the time) from the three other low-probability alternatives (rewarded 25% of the time). Performance was monitored longitudinally, encompassing both a baseline period and the duration of CORT or vehicle treatments. Both cohorts were subsequently screened for anxio-depressive behaviors and evaluated on their capacity for object and spatial memory acquisition. This was assessed using Novel Object Recognition (NOR) and the Radial Arm Maze (RAM). Furthermore, cognitive flexibility was measured via a spatial reversal learning task in the RAM, where animals were required to relocate a food reward after successfully mastering its initial location. Corticosterone-treated mice of both cohorts exhibited anxiety- and depressive-like behaviors in standard behavioral assays used to screen anxiolytic and antidepressant compounds. In the PRD cohort, CORT-treated mice exhibited greater preference for the most rewarding option. Computational modeling via Bayesian trial-by-trial analysis further revealed that this increased preference for the optimal choice stemmed from a rigid reliance on previously acquired associations, which occurred at the expense of integrating deceptive reinforcement experiences. Similar cognitive inflexibility was mirrored using RAM, where CORT mice previously subjected to the PRD struggled to re-locate food when the baited arm was changed. Interestingly, the same mice successfully learned to initially locate the food. Preserved learning ability was similarly observed in the NOR test. Impairments in learning emerged only in CORT-treated mice lacking prior PRD experience. Our results interestingly dissociate corticosterone-induced learning and relearning deficits, suggesting that chronic stress may alters relearning potentially independently of its impact on learning. We are currently utilizing this framework to isolate neural biomarkers involved in memory dynamics, aiming to uncover the molecular basis for the dissociation between stress-induced deficits in learning and relearning. Identifying these targets is a critical step toward developing specialized pro-cognitive therapies for treatment-resistant depression.

References

1. World Health Organization. World Mental Health Report: Transforming Mental Health for All. WHO, 2022.
2. American Psychiatric Association Diagnostic and statistical manual of mental disorders: 5th Edn. Washington, DC: (2013)
3. Conradi HJ, Ormel J, de Jonge P (2011) Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study.Psychol Med. Jun; 41(6):1165-74.
4. Hack LM, Tozzi L, Zenteno S, Olmsted AM, Hilton R, Jubeir J, Korgaonkar MS, Schatzberg AF, Yesavage JA, O’Hara R, Williams LM (2023) A Cognitive Biotype of Depression and Symptoms, Behavior Measures, Neural Circuits, and Differential Treatment Outcomes: A Prespecified Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 6(6):e2318411.
5. David DJ, Samuels BA, Rainer Q, Wang JW, Marsteller D, Mendez I, Drew M, Craig DA, Guiard BP, Guilloux JP, Artymyshyn RP, Gardier AM, Gerald C, Antonijevic IA, Leonardo ED, Hen R. (2009) Neurogenesis-dependent and -independent effects of fluoxetine in an animal model of anxiety/depression. Neuron. 62(4):479-93.