Effects of maternal social isolation on adult rodent offspring cognition.

Prenatal experiences can influence offspring physiology and behaviour through the lifespan. Various forms of prenatal stress impair adult learning and memory function and can lead to increased occurrence of anxiety and depression. Clinical work suggests that prenatal stress and maternal depression lead to similar outcomes in children and adolescents, however the long-term effects of maternal depression are less established, particularly in well controlled animal models. Social isolation is common in depressed individuals and during the recent COVID-19 pandemic. Accordingly, for this study we were interested in the effects of maternal stress induced via social isolation on adult offspring cognitive functions including spatial, stimulus-response, and emotional learning and memory that are mediated by different networks centered on the hippocampus, dorsal striatum, and amygdala, respectively. Tasks included a discriminative contextual fear conditioning task and cue-place water task. Pregnant dams in the social isolation group were single housed prior to and throughout gestation. Once offspring reached adulthood the male offspring were trained on a contextual fear conditioning task in which rats were trained to associate one of two contexts with an aversive stimulus and the opposing context remained neutral. Afterwards a cue-place water task was performed during which they were required to navigate to both a visible and invisible platform. Fear conditioning results revealed that the adult offspring of socially isolated mothers, but not controls, were impaired in associating a specific context with a fear-inducing stimulus as assessed by conditioned freezing and avoidance. Results from the water task indicate that adult offspring of mothers that were socially isolated showed place learning deficits but not stimulus-response habit learning on the same task. These cognitive impairments, in the offspring of socially isolated dams, occurred in the absence of maternal elevated stress hormone levels, anxiety, or altered mothering. Some evidence suggested that maternal blood-glucose levels were altered particularly during gestation. Our results provide further support for the idea that learning and memory networks, centered on the amygdala and hippocampus are particularly susceptible to the negative impacts of maternal social isolation and these effects can occur without elevated glucocorticoid levels associated with other forms of prenatal stress.

Comparison of the effects of repeated exposures to predictable or unpredictable stress on the behavioural expression of fear in a discriminative fear conditioning to context task.

For this series of experiments, we wanted to investigate issues related to stress and learning. First, we wanted to determine if unpredictable stress might foster generalized fear responses more than predictable stress. Second, we wanted to evaluate how repeated stress might influence a rat's ability to learn what context predicts and an aversive event. Our first hypothesis was that unpredictable stress would result in generalized fear responses compared to predictable stress and these effects would worsen over repeated stress cycles. Our second hypothesis was that stress, regardless of type, would result in enhanced discriminative fear conditioning to context, a measure of fear learning. Accordingly, two groups of rats received 14-day restraint stress with one group receiving predictable while the other group received unpredictable stress. Following these experimental manipulations, both groups were given a recovery period and then an assessment of fear-based context discriminative behaviour was performed. This stress-recovery cycle was repeated, and fear conditioning was again assessed. After a single stress-recovery cycle discriminative fear conditioning to context was not impaired for either group. However, we did find that unpredictable stress facilitated behavioural expression of fear in a fearful context. Following two stress-recovery cycles the unpredictable group exhibited discriminative freezing that was elevated within the paired context, whereas, surprisingly, the predictable group did not exhibit differentiated freezing and instead spent similar amounts of time freezing in both contexts. This pattern of effects suggests that unpredictable chronic stress fostered fearful behaviour in the presence of a threatening context, whereas generalized fear is brought about by repeated predictable stress. This result is the opposite of our hypothesis that unpredictable stress would result in generalized fear. Taken together these results show that certain types of stressful experiences (unpredictable) enhance discriminative fear conditioning to context and stress over a longer period can produce generalized fear, but surprisingly in the predictable and not unpredictable condition.

Adolescent THC exposure does not sensitize conditioned place preferences to subthreshold d-amphetamine in male and female rats.

The acute effects of marijuana consumption on brain physiology and behaviour are well documented, but the long-term effects of its chronic use are less well known. Chronic marijuana use during adolescence is of increased interest, given that the majority of individuals first use marijuana during this developmental stage , and  adolescent marijuana use is thought to increase the susceptibility to abusing other drugs when exposed later in life. It is possible that marijuana use during critical periods in adolescence could lead to increased sensitivity to other drugs of abuse later on. To test this, we chronically administered ∆ 9-tetrahydrocannabinol (THC) to male and female Long-Evans (LER) and Wistar (WR) rats directly after puberty onset. Rats matured to postnatal day 90 before being exposed to a conditioned place preference task (CPP). A subthreshold dose of d-amphetamine, found not to induce place preference in drug naïve rats, was used as the unconditioned stimulus. The effect of d-amphetamine on neural activity was inferred by quantifying cfos expression in the nucleus accumbens and dorsal hippocampus following CPP training. Chronic exposure to THC post-puberty had no potentiating effect on a subthreshold dose of d-amphetamine to induce CPP. No differences in cfos expression were observed. These results show that chronic exposure to THC during puberty did not increase sensitivity to a sub-threshold dose of d-amphetamine in adult LER and WR rats. This supports the concept that THC may not sensitize the response to all drugs of abuse.

Evidence of a role for orbital prefrontal cortex in preventing over-generalization to moderate predictors of biologically significant events.

The mammalian brain is specialized to acquire information about environmental predictors of biologically significant events. However, environments contain an array of stimuli from which animals must ascertain which ones are meaningful in the current situation. This kind of uncertainty is inherent in the discriminative fear conditioning to context task (DFCTC) during which rats are trained to associate one context with foot-shock and another distinct context with no event. Although the contexts differ on several dimensions, they also share similarities making some cues perfect predictors, but others moderate predictors. Appropriate responding requires animals to determine which cues are relevant in the current situation and the ability to constrain their responses only to those perfect predictors. The orbital prefrontal cortex (OPFC) is thought to modulate this function as OPFC lesions result in over-generalization during DFCTC. Two experiments were conducted; the first was intended to dissociate the role of the OPFC in acquisition and expression of DFCTC, and the second intended to determine if the OPFC will also function to constrain responses during an appetitive version of DFCTC. We found that inactivation of the OPFC prior to assessment measures resulted in generalized responses on the appetitive and aversive task, however, these effects may be more prominent during the aversive task. Despite generalization during activity testing, rats were able to discriminate between the two contexts during preference. These results point to a broader role for the OPFC constraining responses to perfect predictors of biologically significant events in uncertain contexts.