A major objective of this study was to characterize CRS-induced deficits in motivational drive. As expected CRS-exposed animals lost their preference for saccharin, but also failed to avoid a bitter quinine solution (Figure ). A similar phenomenon has been reported in rhesus monkeys following maternal deprivation [31
]. This study proposed that in addition to producing anhedonia, some chronic stress paradigms may decrease motivation for appetitive stimuli in general [31
]. Deficits in the sucrose and saccharin preference tests have been reliably used as measures of anhedonia [24
], which is defined as the inability to experience pleasure in previously enjoyable activities such as eating, exercising, socializing and sex [32
]. The saccharin preference deficit coupled with the lack of quinine aversion may also indicate apathy, a lack of interest in surroundings, social withdrawal and loss of motivation and initiative [35
]. Apathy, on its own, or when co-morbid with depression poses a challenge to clinicians due to their overlapping symptomatology and frequent co-occurrence [3
]. Identifying apathy requires differentiation between loss of initiation versus loss of ability and emotional indifference versus a primary mood disturbance [7
]. Modeling apathy is important since it does not respond similarly to treatment options for anhedonia [37
]. Accordingly, despite their overlapping symptomatology, there is accumulating evidence that apathy and anhedonia may have different underlying alterations in brain circuits [3
We show that loss of motivational drive in CRS-exposed animals in the saccharin preference test can transfer to a decrease in motivation for an alternative appetitive stimulus. First, we showed that CRS-exposed animals showed normal habituation and dishabituation to three different odors, confirming intact olfactory senses (Figure ). However, we observed a significant decrease in interest for estrous urine (Figure ), suggesting that these animals exhibit deficits in motivational drive. CRS-exposed animals also show lack of motivation in a nest-building paradigm [35
] and decreases in home-cage exploratory behaviors. For example, we saw significant differences in total time spent rearing up, hanging cuddled and sniffing (Table ), and in patterns of diurnal activity. Since alterations in sleep and circadian rhythms play a critical role in the pathophysiology of numerous neuropsychiatric disorders[33
], the ability to model circadian alterations is a useful experimental tool.
It has been suggested that apathy may reflect an interaction between cholinergic deficiency and subsequent neurological changes in limbic regions [42
]. Thus, we asked whether deltaFosB accumulation in the MS/vDB, which constitutes the major cholinergic projection to the hippocampal formation, cingulate cortex and the hypothalamus [29
] could be influencing cholinergic signaling. AChE-I treatment reduces incidence of apathy and improves functioning in patients who present with cholinergic disturbances in limbic and paralimbic cortices [10
], and restoration of function in these brain regions may underlie the behavioral response to AChE-Is [9
]. In AD, functional loss is thought to be a consequence of neuronal loss in cholinergic nuclei, and it has previously been reported that CRS can result in hippocampal atrophy [44
]. However, it appears that cholinergic function in our model may be altered via changes resulting from alterations in plasticity as opposed to neuronal loss because levels of the cholinergic cell marker p75NTR
are unchanged between control and CRS-exposed animals and there are no appreciable changes in regional volume between control and CRS-exposed animals (KM and RJS, unpublished observations).
It is also possible that the behavioral effects of phenserine in our model result from activation of cholinergic interneurons in areas implicated in motivation and reward. For example, it has been shown that the AChE-Is galantamine and donepezil lead to increased dopamine release in NAcc [45
]. Control animals show a robust increase in immediate early gene activation in the NAcc after being exposed to a motivating stimulus, i.e. estrous urine (Figure ), but this increase is lost in CRS-exposed animals. However, phenserine administration rescued this deficit, suggesting that cholinergic facilitation may restore dopaminergic function in the CRS-exposed NAcc. This restorative function could contribute to phenserine's role in behavioral rescue of motivational drive in CRS-exposed animals (Figure ).
The focus of the experiments with phenserine was to determine whether an anticholinesterase had utility in reversing selected CRS-induced phenotypes rather than determining the effect of the drug in a naïve population. However, it remains a caveat of our studies that our study did not include a control group to look at the effects of phenserine in a non-CRS exposed population. Thus, it is possible that the effects of phenserine may not be limited to animals exposed to CRS, but may also have similar effects on a control population.