Interaction of STDP and metaplasticity in modelling heterosynaptic plasticity.

Although neuroscientists have still not found a comprehensive mechanism to underlie learning and memory, many investigations suggest that long term potentiation (LTP) and long term depression (LTD) are involved in establishment of learning and memory. As a consequence of certain neural activity, neurons need to modulate the activity of the synapse or the properties of ion channels, therefore, they use a mechanism called homeostatic plasticity to balance their activity and control their firing rate. Two forms of plasticity phenomena that are necessary for plasticity regulation are homosynaptic and heterosynaptic plasticity. In the dentate granule cell, induction of homosynaptic LTP in the activated pathway is accompanied by heterosynaptic LTD in the inactivated pathway. Because, the dentate granule cell shows changes in synaptic strengths, we used this cell to test the following hypotheses. The first hypothesis we propose is, with plasticity and metaplasticity models introduced in this thesis, and the modification of an average postsynaptic spike, we can reproduce homosynaptic LTP and concurrent heterosynaptic LTD. The second hypothesis is the metaplasticity generated after a high frequency stimulation (HFS) reduces the level of synaptic plasticity caused by a second HFS. To test these hypotheses we use computer simulation and combine the nearest-neighbor spike time dependent plasticity (STDP) and metaplasticity rules accompanied with noisy spontaneous activity and the nine compartmental model of a granule cell. For this study we use the experimental data from Abraham et al.(2001), Abraham et al. (2007) and Bowden et al. (2012). With the method mentioned above our model is able to reproduce homosynaptic LTP in the activated pathway and heterosynaptic LTD in the neighboring inactivated pathway. We also show, due to the metaplasticity effects of the plasticity generated from the first HFS, the same magnitude of LTP and LTD will not occur in both pathways during the second HFS. Our finding supports the assertion that the combination of our metaplasticity and nearest-neighbor STDP rules can be a reliable choice to reproduce synaptic plasticity in the dentate granule cell neuron. Our investigation also supports the idea that metaplasticity modulates synaptic plasticity and prevents the synapse from extreme increases, therefore, the same magnitude of synaptic plasticity will not occur during the second stimulation

Slow Inhibition and Inhibitory Recruitment in the Hippocampal Dentate Gyrus

L’hippocampe joue un rôle central dans la navigation spatiale, la mémoire et l’organisation spatio-temporelle des souvenirs. Ces fonctions sont maintenues par la capacité du gyrus denté (GD) de séparation des patrons d'activité neuronales. Le GD est situé à l’entrée de la formation hippocampique où il reconnaît la présence de nouveaux motifs parmi la densité de signaux afférant arrivant par la voie entorhinale (voie perforante). Le codage parcimonieux est la marque distinctive du GD. Ce type de codage est le résultat de la faible excitabilité intrinsèque des cellules granulaires (CGs) en combinaison avec une inhibition locale prédominante. En particulier, l’inhibition de type « feedforward » ou circuit inhibiteur antérograde, est engagée par la voie perforante en même temps que les CGs. Ainsi les interneurones du circuit antérograde fournissent des signaux GABAergique aux CGs de manière presque simultanée qu’elles reçoivent les signaux glutamatergiques. Cette thèse est centrée sur l’étude des interactions entre ces signaux excitateurs de la voie entorhinale et les signaux inhibiteurs provenant des interneurones résidant dans le GD et ceci dans le contexte du codage parcimonieux et le patron de décharge en rafale caractéristique des cellules granulaires. Nous avons adressé les relations entre les projections entorhinales et le réseau inhibitoire antérograde du GD en faisant des enregistrements électrophysiologiques des CG pendant que la voie perforante est stimulée de manière électrique ou optogénétique. Nous avons découvert un nouvel mécanisme d’inhibition qui apparait à délais dans les CGs suite à une stimulation dans les fréquences gamma. Ce mécanisme induit une hyperpolarisation de longue durée (HLD) et d’une amplitude prononce. Cette longue hyperpolarisation est particulièrement prolongée et dépasse la durée d’autres types d’inhibition transitoire lente décrits chez les CGs. L’induction de HLD crée une fenêtre temporaire de faible excitabilité suite à laquelle le patron de décharge des CGs et l’intégration d’autres signaux excitateurs sont altérés de manière transitoire. Nous avons donc conclu que l’activité inhibitrice antérograde joue un rôle central dans les processus de codage dans le GD. Cependant, alors qu’il existe une multitude d’études décrivant les interneurones qui font partie de ce circuit inhibiteur, la question de comment ces cellules sont recrutées par la voie entorhinale reste quelque peu explorée. Pour apprendre plus à ce sujet, nous avons enregistré des interneurones résidant iii dans la couche moléculaire du GD tout en stimulant la voie perforante de manière optogénétique. Cette méthode de stimulation nous a permis d’induire la libération de glutamate endogène des terminales entorhinales et ainsi d’observer le recrutement purement synaptique d’interneurones. De manière surprenante, les résultats de cette expérience démontrent un faible taux d’activation des interneurones, accompagné d’un tout aussi faible nombre total de potentiels d’action émis en réponse à la stimulation même à haute fréquence. Ce constat semble contre-intuitif étant donné qu’en générale on assume qu’une forte activité inhibitrice est requise pour le maintien du codage parcimonieux. Tout de même, l’analyse des patrons de décharge des interneurones qui ont été activés a fait ressortir la prééminence de trois grands types: décharge précoce, retardée ou régulière par rapport le début des pulses lumineux. Les résultats obtenus durant cette thèse mettent la lumière sur l’important conséquences fonctionnelles des interactions synaptique et polysynaptique de nature transitoire dans les réseaux neuronaux. Nous aimerions aussi souligner l’effet prononcé de l’inhibition à court terme du type prolongée sur l’excitabilité des neurones et leurs capacités d’émettre des potentiels d’action. De plus que cet effet est encore plus prononcé dans le cas de HLD dont la durée dépasse souvent la seconde et altère l’intégration d’autres signaux arrivants simultanément. Donc on croit que les effets de HLD se traduisent au niveau du réseaux neuronal du GD comme une composante cruciale pour le codage parcimonieux. En effet, ce type de codage semble être la marque distinctive de cette région étant donné que nous avons aussi observé un faible niveau d’activation chez les interneurones. Cependant, le manque d’activité accrue du réseau inhibiteur antérograde peut être compensé par le maintien d’un gradient GABAergique constant à travers le GD via l’alternance des trois modes de décharges des interneurones. En conclusion, il semble que le codage parcimonieux dans le GD peut être préservé même en absence d’activité soutenue du réseau inhibiteur antérograde et ceci grâce à des mécanismes alternatives d’inhibition prolongée à court terme.The hippocampus is implicated in spatial navigation, the generation and recall of memories, as well as their spatio-temporal organization. These functions are supported by the processes of pattern separation that occurs in the dentate gyrus (DG). Situated at the entry of the hippocampal formation, the DG is well placed to detect and sort novelty patterns amongst the high-density excitatory signals that arrive via the entorhinal cortex (EC). A hallmark of the DG is sparse encoding that is enabled by a combination of low intrinsic excitability of the principal cells and local inhibition. Feedforward inhibition (FFI) is recruited directly by the EC and simultaneously with the granule cells (GCs). Therefore, FFI provides fast GABA release and shapes input integration at the millisecond time scale. This thesis aimed to investigate the interplay of entorhinal excitatory signals with GCs and interneurons, from the FFI in the DG, in the framework of sparse encoding and GC’s characteristic burst firing. We addressed the long-range excitation – local inhibitory network interactions using electrophysiological recordings of GCs – while applying an electrical or optogenetic stimulation of the perforant path (PP) in the DG. We discovered and described a novel delayed-onset inhibitory post synaptic potential (IPSP) in GCs, following PP stimulation in the gamma frequency range. Most importantly, the IPSP was characterized by a large amplitude and prolonged decay, outlasting previously described slow inhibitory events in GCs. The long-lasting hyperpolarization (LLH) caused by the slow IPSPs generates a low excitability time window, alters the GCs firing pattern, and interferes with other stimuli that arrive simultaneously. FFI is therefore a key player in the computational processes that occurs in the DG. However, while many studies have been dedicated to the description of the various types of the interneurons from the FFI, the question of how these cells are synaptically recruited by the EC remains not entirely elucidated. We tackled this problem by recording from interneurons in the DG molecular layer during PP-specific optogenetic stimulation. Light-driven activation of the EC terminals enabled a purely synaptic recruitment of interneurons via endogenous glutamate release. We found that this method of stimulation recruits only a subset of interneurons. In addition, the total number of action potentials (AP) was surprisingly low even at high frequency stimulation. This result is counterintuitive, as strong and persistent inhibitory signals are assumed to restrict GC v activation and maintain sparseness. However, amongst the early firing interneurons, late and regular spiking patterns were clearly distinguishable. Interestingly, some interneurons expressed LLH similar to the GCs, arguing that it could be a commonly used mechanism for regulation of excitability across the hippocampal network. In summary, we show that slow inhibition can result in a prolonged hyperpolarization that significantly alters concurrent input’s integration. We believe that these interactions contribute to important computational processes such as sparse encoding. Interestingly, sparseness seems to be the hallmark of the DG, as we observed a rather low activation of the interneuron network as well. However, the alternating firing of ML-INs could compensate the lack of persistent activity by the continuous GABA release across the DG. Taken together these results offer an insight into a mechanism of feedforward inhibition serving as a sparse neural code generator in the DG

The role of calcium-permeable AMPA receptors and arc in secreted amyloid precursor protein alpha-mediated plasticity

The orchestrated regulation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-subtype of glutamate receptors by neuronal activity and neuromodulators is critical to the expression of both long-term potentiation (LTP) and memory. In particular, GluA1-containing, Ca2+-permeable AMPAR (CP-AMPAR) comprise a unique role in these processes due to their transient, activity-regulated expression at the synapse. Importantly, many of the mechanisms which govern these processes are negatively affected in neurodegenerative disorders such as Alzheimer’s disease, suggesting that understanding the mode of action of neuromodulatory molecules may reveal much needed novel therapeutic interventions. Secreted amyloid precursor protein-alpha (sAPPα), a metabolite of the parent amyloid precursor protein (APP) has been previously shown to enhance hippocampal LTP and facilitate memory formation. Accordingly, we hypothesised that sAPPα may act via modulation of AMPAR synthesis and cell surface expression. Using primary hippocampal neurons grown in culture, we found that sAPPα (1 nM) differentially regulates the expression of cell surface GluA1-, GluA2-, and GluA3-containing AMPAR. Interestingly, using fluorescent non-canonical amino acid tagging with proximity ligation assay (FUNCAT-PLA), we found that short-term sAPPα treatments (1 nM, 30 min) rapidly enhanced the cell surface expression of newly synthesised extrasynaptic GluA1-, but not GluA2-containing AMPAR, while long-term treatments of sAPPα (1 nM, 120 min) increased levels of pre-existing GluA1/2-containing heteromers at the cell surface, indicating a dynamic regulation of distinct AMPARs following treatment. Moreover, using electrophysiology in area CA1 of acute hippocampal slices, we provide evidence that the expression of CP-AMPAR is important in the induction of sAPPα-enhanced LTP. Using immunocytochemistry and siRNA knockdown, we provide evidence that internalization of CP-AMPARs may be governed, at least in part by sAPPα-driven expression of the activity-regulated cytoskeletal-associated protein (Arc). Further, we show that Arc expression is not induced by the related APP metabolite sAPPβ, but is dependent on synergistic activation of N-Methyl-D-Aspartate and α7-nicotinic acetylcholine receptors, as well as downstream activation of CaMKII, MAPK, and PKG. Together, these findings suggest that application of sAPPα to hippocampal neurons engages a cascade of mechanisms which enhance the synthesis and expression of AMPAR and Arc protein, in the regulation of synaptic strength and the expression of hippocampal LTP. These experiments expand upon our current knowledge underlying mechanisms of synaptic plasticity in hippocampal neurons

Testing the Network Reset Hypothesis: Noradrenergic Modulation of Hippocampal Representations

The locus coeruleus (LC) responds to salience cues, including novelty, and sends a major noradrenergic projection to the hippocampal formation (HF). Novelty-associated LC activation may help to sculpt contextual representations in the HF, but modulatory influence of norepinephrine (NE) over HF representations remains poorly understood. One possible mechanism is that NE provides a “reset” signal causing the HF to recruit distinct neural populations, thereby providing a molecular switch to dictate if hippocampal circuits should generate new representations or update existing ones to incorporate novel information. This hypothesis suggests that NE release should cause the HF to recruit a unique population even in the presence of the same stimuli an animal has just experienced, a phenomenon referred to as “global remapping”. The compartmental expression of immediate early genes (i.e. arc & zif268) allowed us to test this by mapping the activity history of individual neurons as animals engaged in spatial processing following LC-NE manipulation. Recruitment of new neurons is part of the memory encoding process involved in separating memories. Tasks involving memory retrieval require reactivation of representations formed during encoding. If those representations “remapped” (i.e. a new cellular ensemble was recruited, rather than reactivation of the cells comprising the previously formed representation), this should theoretically result in a retrieval error. Therefore, switching the system back to a state of encoding would prove maladaptive in situations where retrieval is necessary to perform a task, unless new information was at hand. We hypothesize that NE resets the system causing the HF to move from a state of retrieval back to encoding when it is necessary, when novel information needs to be incorporated. This hypothesis suggests the effect of modulating NE on memory critically depends on the stage of training. To further understand how NE modulation of hippocampal circuits affects spatial memory, we tested whether infusions of the β-adrenergic agonist isoproterenol would impair working and reference memory retrieval (i.e., switching the system back to encoding when it is maladaptive) and in contrast, promote cognitive flexibility thus improving reversal learning (i.e., switching the system back to encoding when it is adaptive)

Investigation Of The Spatiotemporal Dynamics Of Camp And Pka Signaling And The Role Of Hcn4 Subunits In Anxiety-Related Behavior And Memory

In the hippocampus, long-term memory and synaptic plasticity occur through a series of coordinated intracellular signaling cascades that strengthen and stabilize subsets of synaptic connections while leaving thousands of others unaltered. Therefore, understanding how molecular signals are accurately transmitted is critical to understanding how hippocampal neurons store information. Molecules like cAMP and protein kinase A are critical components of memory and plasticity, but it is unclear how these diffusible signals are dynamically regulated to achieve the spatial and temporal specificity that underlies pathway-specific plasticity. Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels are ion channels that are modulated by cAMP and are known to regulate the spatial and temporal dynamics of excitatory postsynaptic potentials. HCN1 and HCN2 subunits have been implicated in memory, plasticity and anxiety-related behaviors, but the role for HCN4 subunits remains untested. In Chapter 1, I review the role of cAMP signaling in hippocampal synaptic plasticity and memory consolidation with emphasis on the molecular mechanisms regulating cAMP, PKA and HCN channels. In Chapter 2, I combine live two-photon imaging of genetically-encoded fluorescent FRET sensors and computational modeling to investigate the molecular mechanisms regulating the spatiotemporal dynamics of cAMP and PKA activity in hippocampal neurons during stimulation of β-adrenergic receptors. Results suggest that the ratio between adenylyl cyclase and phosphodiesterase-4 scales with neuronal compartment size to maintain basal cAMP levels and produce rapid-onset, high-amplitude cAMP transients in small compartments. Conversely, imaging experiments show that PKA activity is greater in large neuronal compartments and modeling suggests that compartmental differences in PKA activity depend on the concentration of protein phosphatase and not on the concentration of PKA substrates or PKA holoenzyme. In Chapter 3, I use recombinant adeno-associated viruses and shRNA-mediated silencing of HCN4 subunits to examine their role in anxiety, memory, and contextual fear extinction. Results from a battery of behavioral assays suggest that reduction of HCN4 subunits increases anxiety-related behavior, but does not affect object-location memory or contextual fear conditioning. Together, my thesis work provides novel insight into the molecular mechanism regulating the spatiotemporal dynamics of cAMP/PKA signaling and provides suggests a role for HCN4 subunits in anxiety-related behavior

Dual coding with STDP in a spiking recurrent neural network model of the hippocampus.

The firing rate of single neurons in the mammalian hippocampus has been demonstrated to encode for a range of spatial and non-spatial stimuli. It has also been demonstrated that phase of firing, with respect to the theta oscillation that dominates the hippocampal EEG during stereotype learning behaviour, correlates with an animal's spatial location. These findings have led to the hypothesis that the hippocampus operates using a dual (rate and temporal) coding system. To investigate the phenomenon of dual coding in the hippocampus, we examine a spiking recurrent network model with theta coded neural dynamics and an STDP rule that mediates rate-coded Hebbian learning when pre- and post-synaptic firing is stochastic. We demonstrate that this plasticity rule can generate both symmetric and asymmetric connections between neurons that fire at concurrent or successive theta phase, respectively, and subsequently produce both pattern completion and sequence prediction from partial cues. This unifies previously disparate auto- and hetero-associative network models of hippocampal function and provides them with a firmer basis in modern neurobiology. Furthermore, the encoding and reactivation of activity in mutually exciting Hebbian cell assemblies demonstrated here is believed to represent a fundamental mechanism of cognitive processing in the brain

Anatomical Characterization of the Type-1 cannabinoid receptors in specific brain cell populations of mutant mice

151 p.The Cannabinoid Type I receptor protein (CB1) expression in the hippocampus of rescue mice modified to express the gene exclusively in specific brain cell types: such as dorsal telencephalic glutamatergic neurons, or GABAergic neurons have been analysed. Furthermore, aiming at knowing the exact anatomical distribution of the astroglial CB1 receptors with respect to the excitatory and inhibitory synapses, the CB1 receptor expression in astrocytes of mouse expressing CB1 receptor only in astrocytes and mutant mouse expressing the protein hrGFP into astrocytes (that allows for better detection of the astrocytic processes) have been also investigated. The results showed that the majority of the hippocampal synapses surrounded by CB1 receptor immunopositive astrocytes in the 400-800 nm range are of excitatory nature. Moreover, the CB1 receptor rescue mutant mice characterized in this Doctoral Thesis have proven 1) to express CB1 receptors in specific brain cell types; 2) the re-expression is limited to the particular brain cell populations; 3) the endogenous levels of CB1 receptors are maintained in the brain cell types re-expressing the receptor. Which makes this mutant mice excellent tools for functional and translational investigations on the role of the CB1 receptors in the normal and diseased brain

Memory prosthesis: is it time for a deep neuromimetic approach?

Memory loss, one of the most dreaded afflictions of the human condition, presents considerable burden on the world’s health care system and it is recognized as a major challenge in the elderly. There are only a few neuro-modulation treatments for memory dysfunctions. Open loop deep brain stimulation is such a treatment for memory improvement, but with limited success and conflicting results. In recent years closed-loop neuropros-thesis systems able to simultaneously record signals during behavioural tasks and generate with the use of inter-nal neural factors the precise timing of stimulation patterns are presented as attractive alternatives and show promise in memory enhancement and restoration. A few such strides have already been made in both animals and humans, but with limited insights into their mechanisms of action. Here, I discuss why a deep neuromimetic computing approach linking multiple levels of description, mimicking the dynamics of brain circuits, interfaced with recording and stimulating electrodes could enhance the performance of current memory prosthesis systems, shed light into the neurobiology of learning and memory and accelerate the progress of memory prosthesis research. I propose what the necessary components (nodes, structure, connectivity, learning rules, and physi-ological responses) of such a deep neuromimetic model should be and what type of data are required to train/ test its performance, so it can be used as a true substitute of damaged brain areas capable of restoring/enhancing their missing memory formation capabilities. Considerations to neural circuit targeting, tissue interfacing, elec-trode placement/implantation and multi-network interactions in complex cognition are also provided

Copying and Evolution of Neuronal Topology

We propose a mechanism for copying of neuronal networks that is of considerable interest for neuroscience for it suggests a neuronal basis for causal inference, function copying, and natural selection within the human brain. To date, no model of neuronal topology copying exists. We present three increasingly sophisticated mechanisms to demonstrate how topographic map formation coupled with Spike-Time Dependent Plasticity (STDP) can copy neuronal topology motifs. Fidelity is improved by error correction and activity-reverberation limitation. The high-fidelity topology-copying operator is used to evolve neuronal topologies. Possible roles for neuronal natural selection are discussed