Hippocampus | EPFL Graph Search

The hippocampus (via Latin from Greek ἱππόκαμπος, 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, and plays important roles in the consolidation of information from short-term memory to long-term memory, and in spatial memory that enables navigation. The hippocampus is located in the allocortex, with neural projections into the neocortex in humans, as well as primates. The hippocampus, as the medial pallium, is a structure found in all vertebrates. In humans, it contains two main interlocking parts: the hippocampus proper (also called Ammon's horn), and the dentate gyrus. In Alzheimer's disease (and other forms of dementia), the hippocampus is one of the first regions of the brain to suffer damage; short-term memory loss and disorientation are included among t

Genetic selection for low glucocorticoid responsiveness recapitulates PTSD-related phenotypes: a behavioral, neuroimaging and sleep-physiology study

Silvia Monari

Humans show inter-individual differences in vulnerability to develop post-traumatic stress disorder (PTSD) following exposure to trauma. Several critical biobehavioral features have been consistently described in PTSD patients, including blunted cortisol levels, smaller hippocampal size, sleep disturbances. However, because of the delay between trauma exposure and the onset of symptoms characteristic of PTSD, only a few longitudinal studies have tried to dissect whether these features constitute pre-trauma risk factors or consequences of the trauma. Enormous effort in animal and human studies has been dedicated to understanding mechanisms of conditioned fear and fear extinction, processes that are at the core of PTSD. However, the same progress has not been translated into psychiatric practice for PTSD. Deepening our understanding of the contribution of key factors to PTSD-related alterations can serve to develop effective treatments.In particular, with regard to low cortisol levels in PTSD pathophysiology, a causative role for blunted glucocorticoid responsiveness in PTSD has not been demonstrated yet.Here, we have addressed this question in lines of Wistar rats genetically-selected for their differential habituation of glucocorticoid responses to stress (LOW-, INTER-, HIGH-CORT Responder rats) and focused on fear extinction, a hallmark of PTSD symptomology, as one of the key features. As a first step, we looked whether divergent trajectories of glucocorticoid responsiveness were associated with brain volume abnormalities, prompted by the influential role of glucocorticoid in brain development. Notably, rats with low or high corticosterone responsiveness exhibit smaller hippocampi, regardless of trauma exposure, compared to rats with normative corticosterone levels. Similarly, the distribution of corticosteroid receptors in the hippocampus presented similarities between the LOW-CR and the HIGH-CR rats with higher mineralocorticoid receptors (MR) and less glucocorticoid receptors (GR). Although LOW- and HIGH-CR rats displayed a similar hippocampal profile at the structural and molecular levels, only LOW-CR male rats exhibited strong deficits in extinction consolidation compared to rats with 'normative' glucocorticoid responses (INTER-CR rats), and showed higher fear response both at few days and at several weeks after trauma exposure. We next tested the causal involvement of corticosterone in the fear extinction consolidation, and found that post-extinction corticosterone treatment markedly prevented the deficits in extinction memory and attenuated fear relapse. In addition, pharmacological inhibition of corticosterone levels during extinction memory consolidation, but not during training, in the INTER-CR rats led to extinction deficits at retrieval one day later. These results indicate that blunted corticosterone levels contribute to confer major vulnerability than having a small hippocampus, and that consolidation processes following extinction are mainly affected by low corticosterone levels.It is well known that glucocorticoids play an important role in memory consolidation processes and that sleep disturbances are a diagnostic criterion of PTSD. Therefore, we investigated in greater detail the sleep architecture in undisturbed condition and during the consolidation period of the extinction phase, which is known to be supported by sleep-dependent processes. In polysomnographic recordings, we found that rats with blunted corticos

EPFL2022

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