Insular cortex processes aversive somatosensory information and is crucial for threat learning

Learning about threats is essential for survival. During threat learning, an innocuous sensory percept such as a tone acquires an emotional meaning when paired with an aversive stimulus such as a mild footshock. The amygdala is critical for threat memory formation, but little is known about upstream brain areas that process aversive somatosensory information. Using optogenetic techniques in mice, we found that silencing of the posterior insula during footshock reduced acute fear behavior and impaired 1- day threat memory. Insular cortex neurons respond to footshocks, acquire responses to tones during threat learning, and project to distinct amygdala divisions to drive acute fear versus threat memory formation. Thus, the posterior insula conveys aversive footshock information to the amygdala and is crucial for learning about potential dangers in the environment.

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

Analysis of taste processing in rat gustatory cortex

Riccardo Accolla

Gustatory perception is a complex phenomenon involving the recognition of sensory properties of a food (taste modality and intensity, flavour, texture, fat content, temperature) as well as its reward value (pleasantness and nutritional value). The sense of taste lies at the core of this process and has the fundamental task of guiding the individual towards the decision on which substances to ingest and which others to reject. Remarkable progress has been made through molecular and genetic manipulations in the understanding of the coding of taste at the receptor level. However, much less is known about the cortical processing of taste sensation and the organizing principles of the gustatory cortex (GC). Functional maps are evident in many sensory regions of the neocortex, where neurons are arranged in spatially distinct networks to process sensory inputs. In contrast, in the GC, the existence of functional domains encoding different taste modalities has not been shown yet. In this thesis we used in vivo optical imaging techniques to investigate the functional architecture of the GC in regard to pure taste attributes (modality and intensity) and stimulus hedonic value (or pleasantness). In a first study we found that four of the primary taste modalities (sweet, bitter, salty and sour) are represented by distinctive spatial patterns, but that no region was specific to a single modality. In addition, we found that two tastants of similar hedonic value (pleasant or unpleasant) activated areas with more common regions than two tastants with opposite hedonic value. To better investigate the role of GC in representing the hedonic value, in a second study we coupled intrinsic imaging with conditioned taste aversion (CTA), a learning paradigm whereby a subject learns to avoid a taste stimulus previously associated with visceral malaise. We imaged intrinsic signals from the rat GC after inducing CTA to a pleasant stimulus (saccharin) and compared the resulting map to the response to a naturally unpleasant compound (quinine). Our results show that saccharin maps undergo plastic changes after CTA acquisition and after the extinction of the aversion, although this second change did not seem to reflect a simple reversal of the CTA acquisition. This result would be consistent with the evidence that extinction represents a new state of learning. Interestingly, this GC maps plasticity appears to be strongly correlated with the behavioral changes in the stimulus hedonic value. When saccharin shifts from attractive (Ctrl) to aversive (CTA acquisition) and attractive again (CTA extinction) its cortical representation changes in its relative position with respect to the pattern of the reference aversive stimulus, becoming highly correlated to the quinine pattern only after the CTA acquisition. In summary, we propose that the specific cortical patterns can be used to discriminate among various taste modalities, according to a spatial model of taste coding. We also show that GC maps reshape following conditioned learning induced by an internal state of malaise. Overall the present thesis provides new evidence for the GC as a site where multiple taste attributes are processed, including taste modality, intensity, aversive memory and hedonic value.

EPFL2007

Learning, Stress and the Role of Personality Profiles in Rats

Basira Salehi, Maria del Carmen Sandi Perez

Stress has been shown to modulate many aspects of physiology and behavior. In particular, substantial work has confirmed that stress is a strong modulator of learning and memory processes. It is more than a century that Yerkes and Dodson have shown that relationship between stress intensity and memory function follows an inverted-U-shaped curve; memory increases with stress to an optimal point, above or below which memory decreases. Despite the great popularity of the Yerkes-Dodson law, the validity of the law has been criticized due to significant methodological problems in the study performed by Yerkes and Dodson (1908) and their data being judged insufficient to substantiate conclusions, among other reasons. Moreover the existing evidence has not yet illustrated this phenomenon under the same experimental conditions for relational learning tasks. On the other hand, stress is not the only factor that modulates cognitive abilities. Different types of learning and memory might be affected by other factors such as individual differences in personality. While the relationship between personality and learning has been studied in human, animal studies addressed to understanding the relationship between personality and learning have been rare. In addition, exposure to stress during pregnancy can have deleterious emotional effects on women. However, the mechanisms underlying these emotional effects are not well understood, and the development of suitable animal models for stress-induced depression in females still remains scarce. The goal of this Thesis was to investigate how stress affects cognitive and emotional processes in different animal models, and to explore the importance of individual differences in the mediation of stress effects. On a first study, we investigated the relationship between stress intensity and memory function. For this purpose cognitive abilities of rats to learn a radial arm water maze were assessed under different stress intensities, using behavioural and endocrine approaches. Our results confirm, for the first time, the existence of an inverted-U-shape memory function according to stressor intensity during the early learning and memory phases in a hippocampus-dependent task. Furthermore, we present evidence that these stress effects are not shown uniformly by all individuals; rather, performance at either the high or the low stress intensities is differentially affected in individuals with different personality-like profiles. In a second study, we investigated whether different personality traits in the Wistar outbred strain of rats were associated with performance in specific types of learning and memory tasks that have been reported to depend on specific brain areas, such as the amygdala, hippocampus and prefrontal cortex (PFC). Using a wide variety of behavioral tests, we identified three personality factors: anxiety, exploration and locomotion. According to our results, the locomotion trait displayed no correlation with learning and memory. However curiosity trait predicted extinction of fear memories and spatial reversal learning, and the anxiety traits was related to extinction of fear. These results suggest that behavioral traits, anxiety and curiosity, might be linked to the functioning of specific brain areas (i.e. amygdala and PFC). Our findings are consistent with recent human studies showing that certain personality traits can predict academic achievement and point out the importance of constructing learning environments that could optimize individual strengths. In a third study, we used a model of stress during pregnancy in an attempt to mirror more closely than other experimental approaches based mainly on movement restraint procedures the human condition where stress is often persistently imposed by a male aggressive partner. For that purpose we used aggressive male rats that cohabitated with (and therefore can be considered a stressor) female rats during their pregnancy and, then, characterized the behaviour of these females after weaning. Similar to effects reported in humans, mother rats displayed anxiety-like and depressive-like behaviours, with the females presenting a high anxiety trait being the more vulnerable to the deleterious effects resulting from exposure to the aggressive male. These results propose an interesting animal model to study the effect of stress during pregnancy. Taken together, our results reinforce the view that stress has a strong impact on cognitive function and emotion. They also stress the importance of taking into account individual differences to characterize individuals with different vulnerability to be affected in both cognitive and emotional domain by exposure to stress. Our approach is novel and original in that it takes into account several behavioural (personality-like) traits simultaneously and shows the importance of different traits for different aspects of the relationship between stress, emotion and cognition. The approaches and findings provide valuable models to address the neurobiological mechanisms underlying stress effects on behavior.

EPFL2010