Stress at learning facilitates memory formation by regulating AMPA receptor trafficking through a glucocorticoid action

Stress and glucocorticoids (GCs) can facilitate memory formation. However, the molecular mechanisms mediating their effects are largely unknown. alpha-Amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid (AMPA) receptor (AMPAR) trafficking has been implicated in the changes in synaptic strength at central glutamatergic synapses associated with memory formation. In cell cultures, corticosterone has been shown to condition the synaptic trafficking of the AMPAR GluA2 subunit. In this study, we investigated the involvement of GluA2 trafficking in the facilitation of learning by stress. Using the water maze spatial task involving different stress levels, mice trained under more stressful conditions (water at 22 degrees C) showed better learning and memory, and higher post-training corticosterone levels, than mice trained under lower stress (water at 30 degrees C). Strikingly, this facilitated learning by stress was accompanied by enhanced synaptic expression of GluA2 AMPARs that was not observed in mice trained under less stressful conditions. Interfering with GC actions by injecting the GC synthesis inhibitor, metyrapone, blocked both the memory facilitation and the enhanced GluA2 trafficking induced by stressful learning. Intracerebroventricular infusion of the peptide, pep2m, that blocks GluA2 synaptic trafficking by interfering with the interaction between N- ethylmaleimide-sensitive factor and GluA2, impaired immediate performance at learning as well as long-term memory retrieval, supporting a causal role for GluA2 trafficking in stress-induced facilitation of spatial learning and memory. Evidence for the involvement of the neural cell adhesion molecule N-cadherin in interaction with GluA2 is also provided. These findings underscore a new mechanism whereby stress can improve memory function.Neuropsychopharmacology advance online publication, 4 November 2009; doi:10.1038/npp.2009.172.

Elucidating the role of neuron-astrocyte metabolic coupling in learning and memory

Monika Tadi

The brain has very high energy demands that are mainly met by the circulating blood glucose to ensure its proper functioning. Thus, it is not surprising that though the human brain weighs only 2- 3% of the body weight, it consumes approximately 25% of total body glucose. “Neuro-energetic coupling" is a unique feature of the brain and refers to the existence of the tight coupling between (neuronal) synaptic brain activity and energy metabolism. The main excitatory neurotransmitter in the brain is glutamate and most of the energy requirements at the cortical level are met through glutamate-mediated neurotransmission, suggesting that there is a close relationship between brain activity, glutamatergic neurotransmission and energy metabolism. Until the 80s, blood-borne glucose was thought to be the sole energy substrate of the brain cells and it was assumed that glucose is metabolized by neurons and astrocytes (a type of glial cell) independently. It is only during the last two decades that the concept of compartmentalization of energy metabolism between neurons and astrocytes has become more obvious. The transfer of lactate from astrocytes to neurons termed as the “astrocyte-neuron lactate shuttle (ANLS)” model proposed by Dr. Pellerin and Prof. Magistretti posits that glutamate released during brain activation activates glycolysis (one of glucose metabolic pathways) in astrocytes leading to lactate (a monocarboxylate) release in the extracellular space, and this astrocytic lactate is then captured and used as an energy substrate by the activated neurons to meet their energy requirements. It includes a complex chain of events involved in neuro-metabolic coupling and supports the preferential use of lactate by activated neurons under conditions of increased energy demands. Higher brain functions such as learning a new task are associated with structural changes in brain and are metabolically demanding necessitating the need of an additional energy supply to meet the neurons increased energy requirement. In this context, the current thesis project aimed to elucidate the contribution of metabolic coupling between astrocytes and neurons, known as “neuron-astrocyte metabolic coupling” to learning and memory formation. Using an in vivo approach combined with behavioral, molecular and gene manipulation techniques in mice, we set out to investigate the role of neuron-astrocyte metabolic coupling, particularly ANLS in cognition. The project was divided into two main parts: In the first part, the expression of glucose metabolism-related genes was investigated during long term memory (LTM) formation in fear-motivated inhibitory avoidance (IA) learning paradigm. Using (14C) 2-Deoxyglucose (2-DG) technique, we first defined the brain areas that are involved in IA LTM formation. This technique provides an indirect measurement of brain activity by measuring glucose uptake in different brain areas during the task. The results of brain metabolic mapping show an increase in glucose utilization in the hippocampus, amygdala, anterior cingulate cortex and pre-limbic and infra-limbic cortical areas. Results from the quantitative analysis of mRNA levels in the dorsal hippocampus at different time point’s following IA task highlight a time dependent, learning specific change in the expression of genes related to glucose metabolism. Specific set of genes involved in the synthesis and degradation of glycogen (brain glucose reserve present only in astrocytes), pyruvate metabolism and pentose phosphate shunt as well as the ANLS were induced following the IA task. These early observations indicate that the metabolic interactions between astrocytes and neurons undergo modifications during a learning process and suggest that these adaptations may play a key role in the establishment of long-term memory. In the second part of research project, we focused on investigating the behavioral consequences of down regulating the expression of Monocarboxylate Transporter 1 (MCT1), a key ANLS related gene, on cognition and higher brain functions. Mice heterozygous for the MCT1 gene (MCT1+/-) were characterized in numerous behavioral paradigms such as general wellbeing, reflexive and motor capabilities. After having established that MCT1+/- mice have no alterations in general emotional state or in locomotion, a battery of behavioral tests was performed to study cognition in these mice. Compared with wild-type control mice, the MCT1+/- mice display normal muscle strength and motor coordination. However, when tested for higher brain functions, the MCT1+/- mice exhibit learning and memory deficits in several learning paradigms/tasks that are hippocampus and / or amygdala dependent. The cognitive impairment observed in the MCT1 heterozygous mice further highlights the importance of ANLS in memory and suggest that disruption of lactate transfer from astrocytes to neurons via the MCT1 results in cognitive impairment. The overall results in this thesis demonstrate that cerebral energy metabolism, and in particular the transfer of lactate from astrocytes to neurons not only provides temporal adaptations in the learning process, but it also plays a fundamental role in memory formation.

EPFL2013

Stress-induced cognitive and psychopathological alterations

Reto Bisaz, Maria del Carmen Sandi Perez

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.

EPFL2009

Effects of NMDA and AMPA receptor antagonists on corticosterone facilitation of long-term memory in the chick

Maria del Carmen Sandi Perez

Long-term memory formation for a weak passive avoidance task in day-old chicks is facilitated by corticosterone administration. Since (i) glutamatergic systems, through different receptor types, play a key role in learning and memory processes, and (ii) glucocorticoids increase glutamate concentrations in learning-related regions of the mammalian brain, we reasoned that glutamatergic activation might be a mechanism by which corticosterone facilitates the formation of an enduring memory. To assess this hypothesis, long-term retention was evaluated in chicks trained on a weak passive avoidance task and intracerebrally injected with NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists (MK-801 and 6-cyano-7-nitroquinoxaline-2,3-dione) with regard to training and corticosterone injection respectively. The results indicated that either of the antagonists prevented the facilitating effect of corticosterone when administered before the training trial, but failed to interfere with the steroid effect when injected before corticosterone administration in the post-training period, suggesting that their early effectiveness was not related to corticosterone-induced actions but to training-triggered mechanisms. In addition, administration of the AMPA antagonist, 5.5 h after training, was also effective in impairing the long-term memory-potentiating effect of corticosterone. These results support the view that corticosterone facilitates the formation of an enduring memory in this learning model, through the modulation of late events during the consolidation period, including the activation of the AMPA receptor type.