Acetylcholinesterase inhibition ameliorates deficits in motivational drive

We assessed behavior as well as regional neuronal activity patterns using FosB immunohistochemistry after exposure to CRS for 6 h/d for a minimum of 21 d. Based on our FosB findings and recent clinical trials, we administered an anticholinesterase to evaluate attenuation of CRS-induced phenotypes.CRS resulted in behaviors that reflect motivational loss and diminished emotional responsiveness. CRS-exposed mice showed differences in FosB accumulation, including changes in the cholinergic basal forebrain system. Facilitating cholinergic signaling ameliorated CRS-induced deficits in initiation and motivational drive and rescued immediate early gene activation in the medial septum and nucleus accumbens.Some CRS protocols may be useful for studying deficits in motivation and apathetic behavior. Amelioration of CRS-induced behaviors with an anticholinesterase supports a role for the cholinergic system in remediation of deficits in motivational drive.Apathy is characterized by severe loss of motivation to participate in activities, social withdrawal and emotional indifference [1]. Apathy shares some overlapping features with depression, but can be distinguished by lack of dysphoric symptoms including sadness, hopelessness and guilt [2,3]. Apathy is a frequent neuropsychiatric syndrome affecting up to 92% of individuals diagnosed with Alzheimer's disease (AD) [4-6], and up to 70% of those with Parkinson's disease (PD) [2,7-10]. Despite its prevalence, relatively little is known about the underlying neuropathology [10]. Stress exposure is an established risk factor for development of neuropsychiatric symptoms [11-14], and it has been established that animal models of chronic stress cause behavioral changes similar to symptoms of depression in humans [15]. Exposure to extreme forms of chronic stress, including time spent in prisoner of war and concentration camps as well as survival of the atomic bombing, has been documented to result in an apathetic syndrome[16-19]. For examp