Chronic stress deficits in reward behaviour co-occur with low nucleus accumbens dopamine activity during reward anticipation specifically

Whilst reward pathologies e.g., anhedonia and apathy, are major and common in stress-related neuropsychiatric disorders, their neurobiological bases and therefore treatment are poorly understood. Functional imaging studies in humans with reward pathology indicate that attenuated BOLD activity in nucleus accumbens (NAc) occurs during reward anticipation/expectancy but not reinforcement; potentially, this is dopamine (DA) related. In mice, chronic social stress (CSS) leads to reduced reward learning and effortful motivation and, here, DA-sensor fibre photometry was used to investigate whether these behavioural deficits co-occur with altered NAc DA activity during reward anticipation and/or reinforcement. In CSS mice relative to controls: (1) Reduced discriminative learning of the sequence, tone-on + appetitive behaviour = tone-on + sucrose reinforcement, co-occurred with attenuated NAc DA activity throughout tone-on and sucrose reinforcement. (2) Reduced effortful motivation during the sequence, operant behaviour = tone-on + sucrose delivery + tone-off / appetitive behaviour = sucrose reinforcement, co-occurred with attenuated NAc DA activity at tone-on and typical activity at sucrose reinforcement. (3) Reduced effortful motivation during the sequence, operant behaviour = appetitive behaviour + sociosexual reinforcement co-occurred with typical NAc DA activity at female reinforcement. Therefore, in CSS mice attenuated NAc DA activity is specific to reward anticipation and as such potentially causal to deficits in learning and motivation. CSS did not impact on the transcriptome of ventral tegmentum DA neurons, suggesting that its stimulus-specific effects on NAc DA activity originate elsewhere in the neural circuitry of reward processing. Overall design: Mice were injected in VTA with two viral vectors, each of which expressed a fluorescent protein, one under the control of the promoter for tyrosine hydroxylase (Th) to label DA neurons (EGFP+), and the other under the control of the promoter for glutamic acid decarboxylase 67 (Gad1) to label GABA interneurons (mScarlet-I+). After recovery, mice underwent CSS (n=5) or CON (n=6) and, after an interval of 3 days, were then euthanized and perfused with PBS for blood-free brain collection. From the frozen brains, coronal sections including the VTA were cut at 10 µm, mounted onto PET membrane slides and dehydrated-fixed. Using laser capture microdissection, samples (Ø=35 µm) of EGFP+ tissue i.e., the putative cell bodies of DA neurons, were collected, whilst simultaneously avoiding any tissue samples that were also m-Scarlet-I+, i.e., overlapping putative cell bodies of GABA interneurons. Per mouse, n = ~500 neurons were collected, pooled, lysed, and RNA extraction and library preparation were followed by RNA sequencing.