Causal Evidence for the Involvement of the Neural Cell Adhesion Molecule, NCAM, in Chronic Stress-Induced Cognitive Impairments

n/

Learning under stress: a role for the neural cell adhesion molecule NCAM

Stress is known to be a potent modulator of brain function and cognition. While prolonged and/or excessive stress generally exerts negative effects on learning and memory processes, acute stress can have differential effects on memory function depending on a number of factors (such as stress duration, stress intensity, timing and the source of the stress, as well as the learning type under study). Here, we have focused on the effects of 'acute' stress, and examined the literature attending to whether the "source of stress" is 'intrinsic' (i.e., when stress is originated by the cognitive task) or 'extrinsic' (i.e., when stress is induced by elements not related to the cognitive task). We have questioned here whether the neural cell adhesion molecule of the immunoglobulin superfamily (NCAM) contributes to the neurobiological mechanisms that translate the effects of these two different stress sources into the different behavioral and cognitive outcomes. NCAM is a cell adhesion macromolecule known to play a critical role in development and plasticity of the nervous system. NCAM and its post-translational modified form PSA- NCAM are critically involved in mechanisms of learning and memory and their expression levels are known to be highly susceptible to modulation by stress. Whereas available data are insufficient to conclude as to whether NCAM mediates extrinsic stress effects on learning and memory processes, we present systematic evidence supporting a key mediating role for both NCAM and PSA-NCAM in the facilitation of memory consolidation induced by intrinsic stress. Furthermore, NCAM is suggested to participate in some of the bidirectional effects of stress on memory processes, with its enhanced synaptic expression involved in facilitating stress actions while its reduced expression being related to impairing effects of stress on memory functio

Age-related cognitive impairments in mice with a conditional ablation of the neural cell adhesion molecule

Most of the mechanisms involved in neural plasticity support cognition, and aging has a considerable effect on some of these processes. The neural cell adhesion molecule (NCAM) of the immunoglobulin superfamily plays a pivotal role in structural and functional plasticity and is required to modulate cognitive and emotional behaviors. However, whether aging is associated with NCAM alterations that might contribute to age-related cognitive decline is not currently known. In this study, we determined whether conditional NCAM-deficient mice display increased vulnerability to age-related cognitive and emotional alterations. We assessed the NCAM expression levels in the hippocampus and medial prefrontal cortex (mPFC) and characterized the performance of adult and aged conditional NCAM-deficient mice and their age-matched wild-type littermates in a delayed matching-to-place test in the Morris water maze and a delayed reinforced alternation test in the T-maze. Although aging in wild-type mice is associated with an isoform-specific reduction of NCAM expression levels in the hippocampus and mPFC, these mice exhibited only mild impairments in working/episodic-like memory performance. However, aged conditional NCAM-deficient mice displayed pronounced impairments in both the delayed matching-to-place and the delayed reinforced alternation tests. Importantly, the deficits of aged NCAM-deficient mice in these working/episodic-like memory tasks could not be attributed to increased anxiety-like behaviors or to differences in locomotor activity. Taken together, these data indicate that reduced NCAM expression in the forebrain might be a critical factor for the occurrence of cognitive impairments during aging

Stress-induced cognitive and psychopathological alterations:functional involvement of the neural cell adhesion molecule (NCAM)

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

A model for the involvement of neural cell adhesion molecules in stress-related mood disorders

Critical interactions between genetic and environmental factors -- among which stress is one of the most potent non-genomic factors -- are involved in the development of mood disorders. Intensive work during the past decade has led to the proposal of the network hypothesis of depression [Castren E: Nat Rev Neurosci 2005;6:241-246]. In contrast to the earlier chemical hypothesis of depression that emphasized neurochemical imbalance as the cause of depression, the network hypothesis proposes that problems in information processing within relevant neural networks might underlie mood disorders. Clinical and preclinical evidence supporting this hypothesis are mainly based on observations from depressed patients and animal stress models indicating atrophy (with basic research pointing at structural remodeling and decreased neurogenesis as underlying mechanisms) and malfunctioning of the hippocampus and prefrontal cortex, as well as the ability of antidepressant treatments to have the opposite effects. A great research effort is devoted to identify the molecular mechanisms that are responsible for the network effects of depression and antidepressant actions, with a great deal of evidence pointing at a key role of neurotrophins (notably the brain-derived neurotrophic factor) and other growth factors. In this review, we present evidence that implicates alterations in the levels of the neural cell adhesion molecules of the immunoglobulin superfamily, NCAM and L1, among the mechanisms contributing to stress-related mood disorders and, potentially, in antidepressant actio

Developmental Neurobiology of the Rat Attachment System and Its Modulation by Stress

Stress is a powerful modulator of brain structure and function. While stress is beneficial for survival, inappropriate stress dramatically increases the risk of physical and mental health problems, particularly when experienced during early developmental periods. Here we focus on the neurobiology of the infant rat’s odor learning system that enables neonates to learn and approach the maternal odor and describe the unique role of the stress hormone corticosterone in modulating this odor approach learning across development. During the first nine postnatal days, this odor approach learning of infant rats is supported by a wide range of sensory stimuli and ensures attachment to the mother’s odor, even when interactions with her are occasionally associated with pain. With maturation and the emergence of a stress- or pain-induced corticosterone response, this odor approach learning terminates and a more adult-like amygdala-dependent fear/avoidance learning emerges. Strikingly, the odor approach and attenuated fear learning of older pups can be re-established by the presence of the mother, due to her ability to suppress her pups’ corticosterone release and amygdala activity. This suggests that developmental changes in stress responsiveness and the stimuli that produce a stress response might be critically involved in optimally adapting the pup’s attachment system to its respective ecological niche

Causal evidence for the involvement of the neural cell adhesion molecule, NCAM, in chronic stress-induced cognitive impairments

In rodents, chronic stress induces long-lasting structural and functional alterations in the hippocampus, as well as learning and memory impairments. The neural cell adhesion molecule (NCAM) was previously hypothesized to be a key molecule in mediating the effects of stress due to its role in neuronal remodeling and since chronic stress diminishes hippocampal NCAM expression in rats. However, since most of the evidence for these effects is correlative or circumstantial, we tested the performance of conditional NCAM-deficient mice in the water maze task to obtain causal evidence for the role of NCAM. We first validated that exposure to chronic unpredictable stress decreased hippocampal NCAM expression in C57BL/6 wild-type mice, inducing deficits in reversal learning and mild deficits in spatial learning. Similar deficits in water maze performance were found in conditional NCAM-deficient mice that could not be attributed to increased anxiety or enhanced corticosterone responses. Importantly, the performance of both the conditional NCAM-deficient mice and chronically stressed wild-type mice in the water maze was improved by post-training injection of the NCAM mimetic peptide, FGLs. Thus, these findings support the functional involvement of NCAM in chronic stress-induced alterations and highlight this molecule as a potential target to treat stress-related cognitive disturbances. (c) 2009 Wiley-Liss, Inc

Role of NCAM in emotion and learning

NCAM is an abundant cell adhesion molecule known to be important during development. Together with its posttranslational modification consisting of the addition of the polysaccharide polysialic acid (PSA), NCAM has been classically implicated in the regulation - among other developmental functions - of neurite outgrowth and stabilization of synaptic connections. A large body of work has also demonstrated that NCAM is required in the adult brain for different behavioral functions. In this review, we focus on those studies that have shown a role of NCAM and PSA-NCAM in the regulation of emotional responses and in the learning and memory processe