Hippocampal representation of touch and sound guided behavior

Understanding the mechanisms by which sensory experiences are stored is a longstanding challenge for neuroscience. Previous work has described how the activity of neurons in the sensory cortex allows rats to discriminate the physical features of an object contacted with their whiskers. But to date there is no evidence about how neurons represent the behavioral significance of tactile stimuli, or how tactile events are encoded in memory. To investigate these issues, we recorded single-unit firing and local field potentials from the CA1 region of hippocampus while rats performed a tactile task. On each trial, the rat touched a plate with its whiskers and, after identifying the texture of the plate, turned to the left or right to obtain its reward. Two textures were associated with each reward location. Over one-third of the sampled neurons encoded the identity of the texture: their firing differed for the two stimuli associated with the same reward location. Over 80 percent of the sampled neurons encoded the behavioral significance of the contacted texture: their firing differed according to the reward location with which it was associated. Texture and reward location signals were present continuously, from the moment of stimulus contact through the entire period of reward collection. The local field potential power spectrum varied across the different phases of behavior, showing that signals of single-units were present within a sequence of different hippocampal states. The influence of location was examined by training rats to perform the same task in different positions within the room. The responses of neurons to a given stimulus in different locations were independent. This was not the case for reward location signals: neurons that carried a signal in one location were more likely to carry a signal in the other location. In summary, during a touch-guided behavior, neurons of the CA1 region represent both non spatial (texture identity) and spatial (reward location) events. Additional experiments were carried out, on another set of rats, to generalize some of the above findings from the tactile to the auditory modality. On each trial, the rat leaned into the gap and heard one of four sounds which were distributed along a vowel continuum from "A" to "I". After identifying the sound, the rat turned to the left or right to obtain its reward. Two sounds were associated with each reward location, and the experiment was repeated on 2 platforms. As in the tactile task, more than 80 percent of neurons represented reward location and more than 25 percent of neurons represented the identity of the sound (the vowel). The role of context on the stimulus and reward location signals was the same as in the tactile experiments. Representations of sounds were independent across 2 platforms but the representations of reward location were not: neurons that carried a signal in one location were more likely to carry a signal in the other location. These responses were absent during passive listening to the sounds

Dynamic coupling between whisking, barrel cortex, and hippocampus during texture discrimination: A role for slow rhythms

Increasing amounts of work have demonstrated that brain rhythms might constitute clocking mechanisms against which to coordinate sequences of neural firing; such rhythms may be essential to the coding operations performed by the local networks. The sequence of operations underlying a tactile discrimination task in rats requires the animal to integrate two streams of information, those coming from the environment and, from reference memory the rules that dictate the correct response. The current study is a follow up on the work which has described the hippocampal representation of the tactile guided task. We have used a well-established texture discrimination task, in which rats have to associate two stimuli with two different reward locations. We placed microelectrodes in primary somatosensory cortex and the CA1 region of hippocampus to perform recordings of spiking activity and local field potentials when the animal touched the discriminandum as well as when he was in a resting state. We also performed recording on an arena in which the animal moved freely and did not perform any task. Earlier work has demonstrated that tactile signals reach the hippocampus during texture discrimination, presumably through the somatosensory cortex. We predicted that neurons in the primary somatosensory cortex (S1) are entrained to the oscillatory theta rhythm that permeates the hippocampus. Our expectation is that such coherence could serve to increase the reliability of synaptic transmission, linking the acquisition of new sensory information with associative processes. We addressed the following issues: Is the timing of action potentials in S1 modulated by the ongoing hippocampal theta rhythm? If so, is the occurrence of this modulation aligned in time to the period in which the hippocampus acquires tactile signals? We also predicted that the 10-Hz whisking that characterizes the acquisition of texture information would be more strongly phase locked to theta rhythm than the whisking in the air that is not accompanied by any explicit tactile task. We speculate that such phase locking could be a means to synchronize sensory and hippocampal processing. The notion that the coordination between brain areas might be related to the rhythmic of sensorimotor cycles is particularly appealing. We have found that the firing of 18% of barrel cells was significantly modulated by hippocampal theta during the half-second period of active tactile discrimination. Importantly, we found that during periods of rest interleaved in the session, neurons significantly decreased the degree of phase-locking with respect to touch. We hypothesize that areas involved with motivational processes as basal ganglia could gate the entrainment during task related epochs. S1 neurons were classified as those excited by contact with the discriminandum, and those not excited by contact. The firing of both sorts of neurons was modulated by CA1 theta rhythm during exploration of the texture. However the theta phase to which they fired preferentially was opposite; contact-responsive neurons tended to fire in the upward phases of the cycle whereas contact non-responsive neurons tended to fire in the downward phase of the cycle suggesting that theta rhythm might have the function of temporally separating sensory cortical neurons according to their functional properties and the information they carry. By clustering touch-sensitive neurons to a certain time window and separating them from \u2018non-informative\u2019 neurons, theta rhythm could increase the efficiency not only of information tranfer to hippocampus but also the efficiency of information encoding/decoding. We also found phase and amplitude relationships between whisking and hippocampal theta during the goal-directed tactile task; the relationships disappear when the animal moves along an open arena, still actively whisking but not engaged in the texture discrimination task. We were able to show, for the first time to our knowledge, that CA1 theta rhythm can exert a behavioral state-dependent modulatory effect on sensory cortex. S1 neuron firing and whisking activity are entrained to hippocampal theta rhythm when the animal collects meaningful tactile information from the environment

Network targets for therapeutic brain stimulation: towards personalized therapy for pain

Precision neuromodulation of central brain circuits is a promising emerging therapeutic modality for a variety of neuropsychiatric disorders. Reliably identifying in whom, where, and in what context to provide brain stimulation for optimal pain relief are fundamental challenges limiting the widespread implementation of central neuromodulation treatments for chronic pain. Current approaches to brain stimulation target empirically derived regions of interest to the disorder or targets with strong connections to these regions. However, complex, multidimensional experiences like chronic pain are more closely linked to patterns of coordinated activity across distributed large-scale functional networks. Recent advances in precision network neuroscience indicate that these networks are highly variable in their neuroanatomical organization across individuals. Here we review accumulating evidence that variable central representations of pain will likely pose a major barrier to implementation of population-derived analgesic brain stimulation targets. We propose network-level estimates as a more valid, robust, and reliable way to stratify personalized candidate regions. Finally, we review key background, methods, and implications for developing network topology-informed brain stimulation targets for chronic pain

Neural correlates of sensation and navigation in the retrosplenial cortex

By virtue of its anatomical connections, the retrosplenial cortex (RSC) is well suited to mediate bidirectional communication between the hippocampal formation and the neocortex. However, what information is encoded in the firing of RSC neurons is largely unclear. I used 2-photon calcium imaging to measure RSC population activity during a goal-directed virtual spatial task that was sometimes complemented by drifting gratings visual stimuli. Over 10% of RSC neurons, mainly in superficial layers, showed place fields with properties similar to CA1 place cells measured in the same task. A distinct subset of neurons (~15%), predominantly in agranular RSC, showed pronounced responses to the visual stimuli. Some of these RSC visual neurons were specifically selective for the speed and direction of visual motion. The results suggest that RSC contains multiple functional cell types distributed differentially across depths and subregions showing responses to external sensory stimulation and internal navigational signals.NERF AIHS NSER

Cortical contributions to landmark integration in the rodent head direction system

Head direction (HD) cells in the rodent brain can use visual information about surrounding landmarks to ‘reset’ their represented orientation, to keep it aligned with the world (a process called landmark anchoring). This implies HD cells receive input from the visual system about the surrounding panorama and its landmarks. Which features in a panorama are used by the HD system? Can HD cells integrate raw luminance input from across the panorama, as might be subserved by subcortical visual processing? Alternatively, do HD cells need discretised landmarks with features, requiring more elaborate visual landmark processing and recognition? I present work addressing how visual information reaches the HD circuit in rats. In the first experiment, we ask whether HD cells require discrete landmarks to anchor to visual panoramas. We record HD cells in a landmark anchoring paradigm using a visual panorama containing a single gradient shifting gradually from black to grey to black. Although there was evidence HD cells could integrate information from this scene, cue control was weak and less reliable than anchoring to visual landmarks with edges. In the second experiment, I present HD cell recordings in rats with lesions of the lateral geniculate nucleus, the thalamic relay of the cortical visual pathway, to test whether subcortical vision is sufficient for landmark-anchoring. HD cells in these animals showed impaired anchoring to cue cards, and lesion extent correlated with the severity of the impairment. Together, these findings indicate that the cortical visual pathway is necessary for intact and stable landmark anchoring to visual cues. Although this process can use entire visual panoramas, it may be more precise if distinct features are available in the scene. Landmark processing in the brain may be complex, and further work could probe whether direct projections from visual cortex provide this information to the HD circuit

Integrative function in rat visual system

A vital function of the brain is to acquire information about the events in the environment and to respond appropriately. The brain needs to integrate the incoming information from multiple senses to improve the quality of the sensory signal. It also needs to be able to distribute the processing resources to optimise the integration across modalities based on the reliability and salience of the incoming signals. This thesis aimed to investigate two aspects of the way in which the brain integrates information from the external environment: multisensory integration and selective attention. The hooded rat was used as the experimental animal model. In Chapter 2 of this thesis, I investigate the multisensory properties of neurons in superior colliculus (SC), a midbrain structure involved in attentive and orienting behaviours. I first establish that in rat SC, spiking activity is elevated by whisker or visual stimuli, but rarely both, when those stimuli are presented in isolation. I then show that visually responsive sites are mainly found in superficial layers whereas whisker responsive sites were in intermediate layers. Finally I show that there are robust suppressive interactions between these two modalities. In Chapter 3, I develop a rodent behavioural paradigm that can easily be paired with electrophysiological measurements. The design is adaptable to a variety of detection and discrimination tasks. Head position is restricted in the central nose-poke without head-fixation and the eyes can be constantly monitored via video camera. In Chapter 4, I ask whether selective spatial visual attention can be demonstrated in rats utilising the paradigms developed in Chapter 3. Selective attention is the process by which brain focuses on significant external events. Does being able to predict the likely side of the stimulus modulate the speed and accuracy of stimulus detection? To address this question, I varied the probability with which the signal was presented on left or right screen. My results suggest that rats have the capacity for spatial attention engaged by top-down mechanisms that have access to the predictability of stimulus location. In summary, my thesis presents a paradigm to study visual behaviour, multisensory integration and selective spatial attention in rats. Over the last decade, rats have gained popularity as a viable animal model in sensory systems neuroscience because of the access to the array of genetic tools and in vivo electrophysiology and imaging techniques. As such the paradigms developed here provide a useful preparation to complement the existing well-established primate models

Use of functional neuroimaging and optogenetics to explore deep brain stimulation targets for the treatment of Parkinson's disease and epilepsy

Deep brain stimulation (DBS) is a neurosurgical therapy for Parkinson’s disease and epilepsy. In DBS, an electrode is stereotactically implanted in a specific region of the brain and electrical pulses are delivered using a subcutaneous pacemaker-like stimulator. DBS-therapy has proven to effectively suppress tremor or seizures in pharmaco-resistant Parkinson’s disease and epilepsy patients respectively. It is most commonly applied in the subthalamic nucleus for Parkinson’s disease, or in the anterior thalamic nucleus for epilepsy. Despite the rapidly growing use of DBS at these classic brain structures, there are still non-responders to the treatment. This creates a need to explore other brain structures as potential DBS-targets. However, research in patients is restricted mainly because of ethical reasons. Therefore, in order to search for potential new DBS targets, animal research is indispensable. Previous animal studies of DBS-relevant circuitry largely relied on electrophysiological recordings at predefined brain areas with assumed relevance to DBS therapy. Due to their inherent regional biases, such experimental techniques prevent the identification of less recognized brain structures that might be suitable DBS targets. Therefore, functional neuroimaging techniques, such as functional Magnetic Resonance Imaging and Positron Emission Tomography, were used in this thesis because they allow to visualize and to analyze the whole brain during DBS. Additionally, optogenetics, a new technique that uses light instead of electricity, was employed to manipulate brain cells with unprecedented selectivity

Role of the hippocampus in goal representation : Insights from behavioural and electrophysiological approaches

The hippocampus plays an important role in spatial cognition, as supported by the location-specific firing of hippocampal place cells. In random foraging tasks, each place cell fires at a specific position (‘place field’) while other hippocampal pyramidal neurons remain silent. A recent study evidenced a reliable extra-field activity in most CA1 place cells of rats waiting for reward delivery in an uncued goal zone. While the location-specific activity of place cells is thought to underlie a flexible representation of space, the nature of this goal-related signal remains unclear. To test whether hippocampal goal-related activity reflects a representation of goal location or a reward-related signal, we designed a two-goal navigation task in which rats were free to choose between two uncued spatial goals to receive a reward. The magnitude of reward associated to each goal zone was modulated, therefore changing the goal value. We recorded CA1 and CA3 unit activity from rats performing this task. Behaviourally, rats were able to remember each goal location and flexibly adapt their choices to goal values. Electrophysiological data showed that a large majority of CA1-CA3 place and silent cells expressed goal-related activity. This activity was independent from goal value and rats’ behavioural choices. Importantly, a large proportion of cells expressed a goal-related activity at one goal zone only. Altogether, our findings suggest that the hippocampus processes and stores relevant information about the spatial characteristics of the goal. This goal representation could be used in cooperation with structures involved in decision-making to optimise goal-directed navigation

Neuromodulated plasticity of the connectivity between the Prefrontal Cortex and the noradrenergic Locus Coeruleus

Incentive stimuli and environmental stressors are encoded at the level of the prefrontal cortex (PFC) circuits, which send their glutamatergic excitatory projections to several neuromodulatory regions, including the Locus Coeruleus (LC), the major source of noradrenaline (NA) for the entire forebrain. Despite the potential implications for NA-mediated regulation of action control and for the etiology of stress-related neuropsychiatric conditions, it remains to be established how LC neuronal activity is shaped by impinging PFC inputs (PFC\uf0e0LC) to affect behavior, and whether these inputs are modulated by in-vivo experience. By combining neurophysiological and optogenetic approaches together with behavioral paradigms in mice, we found that PFC \uf0e0LC stimulation supports learning and retrieval of contextual memory associations. Consistent with the occurrence of plasticity processes at LC synapses, long-lasting modulation of PFC\uf0e0LC projections relies on the endocannabinoid (eCB)-mediated signaling capacity, which is dynamically shaped by context adaptations and stress salience experiences. We also found that eCB-plasticity at PFC \u2192 LC synapses is regulated during the adolescence to adulthood transition. In summary, our results not only dissect the behavioral implications of neuromodulated plasticity at PFC inputs to the LC, but also unveil divergent synaptic substrates during postnatal development, which might be relevant to explain some of the different noradrenergic-mediated response in adolescents and adults. \u200

Exploring the psychobiology of emotions and motivations through computational models

This thesis investigates emotions and motivations on the basis of an operational approach. This approach has both computational and psychobiological roots. Three main directions of research are followed: (1) investigation on the neural substrates of emotional systems though the exploration of the literature about comparative functional anatomy and physiology; (2) definition the relationship between emotion, cognition and behaviour through the exploration of the psychobiological literature about animal models; (3) building of computational models constrained by the sources of information 1 and 2; (4) testing the behaviour of such models within simulated robots acting in simulated environments. The main focus will be on the interaction between the emotional and motivational systems and high level cognitive processes behind adaptive behaviour. The whole study will be informed by the current psychobiological knowledge about the functioning of the neural systems pivoting on amygdala, given that this is considered to be one of the major nodes of interaction between the processing of internal values and the processing about the past, current and future world outside the organism in superior vertebrates