Stress-induced cognitive and psychopathological alterations

Intensive research over the past few years has provided evidence, that stress is a potent modulator of brain function and cognition. In particular cognitive and emotional processes have been shown to be susceptible to modulation by stress. Whereas acute stress and/or a transient activation of the stress system can have beneficial consequences on learning and memory processes, prolonged or extensive stress can induce structural and functional alterations in various brain regions, which are accompanied by cognitive impairments and emotional changes. Moreover, increasing evidence points out that inappropriate stress response and/or control might be associated with the development and exacerbation of a variety of neuropsychiatric disorders. The neural cell adhesion molecule (NCAM), a cell surface macromolecule which is abundantly expressed in the vertebrate nervous system, plays a key role during neural development and has been implicated in activity induced synaptic plasticity as well as cognitive and emotional processes in adulthood. Altered expression of NCAM has been hypothesized to be one of the key events underlying structural and functional alterations in response to stress and accumulating evidence in rodents are showing decreased hippocampal NCAM expression after chronic stress. However, since most of the available evidence for this hypothesis has been either correlational or circumstantial, we aimed here to provide evidence for a causal involvement of NCAM in stress-induced cognitive and emotional disturbances. For this purpose, we evaluated the consequence of 4 weeks of chronic stress in adult wild-type mice on NCAM expression levels in brain regions, known to play a key role in cognition and emotions in a variety of cognitive and emotional tests. We found, that chronically stressed mice have reduced hippocampal NCAM expression levels and display learning and memory impairments, in hippocampus dependent behavioral tasks. Strikingly, similar patterns of cognitive impairments were also found in conditional NCAM-deficient mice, in which the NCAM gene is ablated in the forebrain postnatally. Interestingly, spatial learning and memory impairments of these mice could be recovered by treatments with NCAM mimetic peptides, which are known to potentiate NCAM functioning. Moreover, conditional NCAM-deficient mice displayed increased vulnerability to develop cognitive and emotional disturbances following subchronic stress exposure, a condition which has been shown to induce none (or only slight) structural and behavioral alterations in wild-type rodents. In the amygdala, a brain structure involved in consolidation of emotional memories, NCAM expression was increased in mice exposed to chronic stress. Additionally, chronically stressed mice displayed facilitated auditory fear conditioning, a behavioral task that critically depends on amygdala functions. Contrary, conditional NCAM-deficient mice displayed reduced conditioned auditory fear responses, which indicates a possible involvement of changes in amygdala NCAM expression and altered auditory fear conditioning. Together, the findings of the present study support a functional involvement of alterations in NCAM expression levels in stress-induced cognitive and emotional alterations and highlight this molecule as a potential target for the treatment of stress-related cognitive and emotional disturbances.