Bio-mimetic Spiking Neural Networks for unsupervised clustering of spatio-temporal data

Spiking neural networks aspire to mimic the brain more closely than traditional artificial neural networks. They are characterised by a spike-like activation function inspired by the shape of an action potential in biological neurons. Spiking networks remain a niche area of research, perform worse than the traditional artificial networks, and their real-world applications are limited. We hypothesised that neuroscience-inspired spiking neural networks with spike-timing-dependent plasticity demonstrate useful learning capabilities. Our objective was to identify features which play a vital role in information processing in the brain but are not commonly used in artificial networks, implement them in spiking networks without copying constraints that apply to living organisms, and to characterise their effect on data processing. The networks we created are not brain models; our approach can be labelled as artificial life. We performed a literature review and selected features such as local weight updates, neuronal sub-types, modularity, homeostasis and structural plasticity. We used the review as a guide for developing the consecutive iterations of the network, and eventually a whole evolutionary developmental system. We analysed the model’s performance on clustering of spatio-temporal data. Our results show that combining evolution and unsupervised learning leads to a faster convergence on the optimal solutions, better stability of fit solutions than each approach separately. The choice of fitness definition affects the network’s performance on fitness-related and unrelated tasks. We found that neuron type-specific weight homeostasis can be used to stabilise the networks, thus enabling longer training. We also demonstrated that networks with a rudimentary architecture can evolve developmental rules which improve their fitness. This interdisciplinary work provides contributions to three fields: it proposes novel artificial intelligence approaches, tests the possible role of the selected biological phenomena in information processing in the brain, and explores the evolution of learning in an artificial life system

Neuronal boost to evolutionary dynamics

Standard evolutionary dynamics is limited by the constraints of the genetic system. A central message of evolutionary neurodynamics is that evolutionary dynamics in the brain can happen in a neuronal niche in real time, despite the fact that neurons do not reproduce. We show that Hebbian learning and structural synaptic plasticity broaden the capacity for informational replication and guided variability provided a neuronally plausible mechanism of replication is in place. The synergy between learning and selection is more efficient than the equivalent search by mutation selection. We also consider asymmetric landscapes and show that the learning weights become correlated with the fitness gradient. That is, the neuronal complexes learn the local properties of the fitness landscape, resulting in the generation of variability directed towards the direction of fitness increase, as if mutations in a genetic pool were drawn such that they would increase reproductive success. Evolution might thus be more efficient within evolved brains than among organisms out in the wild

Morphological Correlates Of Synaptic Plasticity After Long Term Potentiation In The Rat Hippocampus

Changes in synapse and neuronal morphology have been reported in the rat hippocampal formation after the induction of long-term potentiation (LTP) of the perforant path, although few studies have investigated such parameters in the maintenance phase of L-LTP. Moreover, the results of investigations of synaptic and neuronal morphometry changes after LTP have varied and this could be due to the methods of analysis employed, the choice of stimulation protocol and or whether an in vitro or in vivo study. This in vivo investigation applied unbiased stereological methods to examine the morphology and morphometry of perforant path-granule cell synapses, in the dentate gyrus, after the induction of LTP. Two controls were employed, the contralateral hemisphere of each animal and the inner molecular layer, where the medial perforant path has little synaptic input. Many previous studies of the first 6Omin post tetanisation have used high frequency stimulation (HFS) to induce LTP however, in this study – to determine whether changes in morphology were due to LTP per se - potentiation was induced by theta burst stimulation (TBS). 45min after the induction of LTP there were no significant differences, between hemispheres, in the mean numerical density (Nv) of axodendritic or axospinous asymmetric synapses, or the mean number of synapses per neuron in the middle molecular layer (MML) of the dentate gyrus. There were no significant differences, between potentiated and non-potentiated tissue, in the Nvs of those asymmetric synapses with perforated or concave profiles. Neither were significant differences following LTP demonstrated in the size of the postsynaptic densities of these synaptic subtypes or the volume density of apposition zone (AZ) area (Sv) of individual, or all, asymmetric axospinous synapses. However, there was a trend towards larger perforated synapses in the potentiated hemisphere and, in both hemispheres, concave and perforated synapses were larger than average. In the inner molecular layer (IML), there were no differences except for a significant decrease in the total AZ volume density in the potentiated hemisphere. This would suggest that any morphological modifications taking place in the induction phase of L-LTP may be restricted to a fraction of synapses in the MML, although perforated synapses appear to be involved. The second part of this study examined morphological correlates 24h after the induction of LTP with TBS and HFS. In the MML after induction of LTP with TBS there were significant increases in the Nv of asymmetric axodendritic synapses and the mean number of axodendritic synapses per neuron. There was an increase in the Nv of axospinous synapses and in the mean number of axospinous synapses per neuron that was not significant. This was reflected in significant increases in the total AZ Sv and in the frequency of macular synapses in the potentiated hemisphere. 24h post tetanisation with HFS, there was a significant difference in the Nv of axospinous synapses in the MML of the potentiated compared to the contralateral hemisphere. There were also significant differences in the frequency of synapses with perforated and concave profiles. There were no significant differences in synaptic morphometric parameters, between hemispheres, in the IML after either of the stimulating regimes. Results from the three animals in each group showing the greatest degree of potentiation, were pooled and demonstrated significant differences in the Nv and mean number of axospinous synapses per neuron. There was also a significant difference in the number of synapses with concave profiles but this was replicated in the IML. The effects of these morphological changes, after LTP induction, on the cellular mechanisms involved and on synaptic efficacy are discussed, and possible reasons for the variable pattern of morphology after different stimulating protocols is considered

Interrogating the Role of Cocaine-Generated Silent Synapses in the Regulation of Cocaine-Associated Memory Dynamics

Drug addiction is an acquired behavioral state that develops progressively through repeated drug experience and is characterized by maladaptive and compulsive behavior associated with drug seeking and taking. Cravings and subsequent drug seeking are often precipitated by the reactivation of memories associated with drug use, which are formed between various external stimuli, or cues, and the rewarding and pleasurable experience of taking the drug. As such, drug addiction is often conceptualized as a pathological form of memory that drives maladaptive behavior. This has spurred intensive investigation into the neural substrates underlying drug-associated memories, with the ultimate goal of targeting these substrates to disrupt drug seeking behaviors. To explore the synaptic underpinnings of cocaine-associated memories, we studied AMPA receptor (AMPAR)-silent excitatory synapses, which are generated in the nucleus accumbens (NAc) by cocaine experience. These synapses functionally mature during withdrawal through the recruitment of AMPARs and contribute to subsequent cocaine seeking behavior, indicating these synapses contribute to the encoding of cocaine-associated memories and behaviors. In this dissertation, we have further investigated the role of cocaine-generated silent synapses in the encoding of cocaine-associated memories by examining their role in regulating the natural dynamics of cocaine-associated memories. Our results demonstrate that dynamic changes in the functional state of cocaine-generated synapses contributes to the natural destabilization and reconsolidation of cocaine-associated memories following memory retrieval, and that disrupting these synaptic dynamics impairs subsequent cocaine seeking behaviors. In addition, we also demonstrate that cocaine-generated synapses contribute to the recruitment and activation of neurons within the NAc associated with cocaine seeking behavior during withdrawal, suggesting they may contribute to the encoding of cocaine-associated memories at the circuit level. Collectively, these findings provide further support to the hypothesis that cocaine-generated synapses serve as discrete synaptic substrates underlying aspects of cocaine-associated memories and behaviors

The role of DKK3 in synapse dynamics in the adult hippocampus and in Alzheimer’s Disease

Synaptic loss highly correlates with cognitive decline in Alzheimer’s Disease (AD). Accumulating evidence implicates deregulation of Wnt signalling in AD pathology and synapse dysfunction. Wnt signalling plays an important role in synapse formation during development and synapse plasticity and maintenance in the adult brain. Recent studies showed that Dickkopf-3 (DKK3), an abundantly expressed Wnt antagonist, is elevated in the cerebral spinal fluid and accumulates in Amyloid beta (Aβ) plaques in AD patients. However, the role of DKK3 in the brain is mostly unexplored. I examined the function of DKK3 in mature synapses and in AD by performing gain- and loss-of-function studies, and using biochemical, molecular and imaging techniques. I showed that DKK3 is present in neurons, synapses, and astrocytes of the adult hippocampus. DKK3 gain-of-function leads to a decrease in excitatory to inhibitory (E/I) synapse ratio, whereas loss-of-function of DKK3 leads to an increase in E/I synapse ratio in the hippocampus. Exploring the role of DKK3 in E/I synaptic changes after long-term depression (LTD), I discovered that DKK3 secretion is increased and that DKK3 is required for the E/I synapse reorganisation after NMDAR-mediated LTD. These findings reveal a previously unknown role of DKK3 in regulating E/I synapse density and advances our knowledge of E/I synapse balance regulation in the adult hippocampus. Investigating the role of DKK3 in AD, I found that DKK3 secretion is increased in the J20 hippocampus, which exhibits decreased E/I synapse ratio. In addition, I showed that DKK3 accumulates in dystrophic neurites around plaques and promotes plaque expansion, possibly through microglia regulation. My results suggest that DKK3 contributes to AD pathology by controlling plaques growth and may further contribute by affecting E/I synapse imbalance in the hippocampus. In summary, these results demonstrate a novel mechanism, by which deficient Wnt signalling contributes to synapse vulnerability and pathology in AD

Contribution of a genetic variant of the Wnt receptor LRP6 to synapse vulnerability in the ageing hippocampus

Synapse dysfunction and loss represent key pathological hallmarks of Alzheimer's disease (AD). Wnt signalling, in particular through the Wnt co-receptor LRP6, has a critical role in maintaining the structural and functional integrity of synaptic connections in the adult brain. LRP6 dysfunction and deficient Wnt signalling compromise synaptic circuits during ageing, contributing to AD pathogenesis. Wnt signalling has been implicated in AD through a genetic link: A common variant of LRP6 (LRP6-Val) based on a single-nucleotide polymorphism (SNP) confers reduced Wnt signalling activity in cell lines and is associated with an increased risk for late-onset AD. However, it is unknown whether LRP6-Val has a functional impact on synapses in the brain. To investigate the LRP6-Val variant in a physiological context, a novel knock-in mouse model was generated for this study. I examined the structure and function of excitatory hippocampal synapses as well as hippocampus-dependent memory function, using a multidisciplinary approach combining cell biology, imaging, electrophysiological and behavioural studies. My findings demonstrate that the LRP6-Val variant compromises Wnt signalling in an age-dependent manner, leading to pre- and postsynaptic structural and functional defects in the ageing hippocampus. Shrinkage of presynaptic terminals and dendritic spines is accompanied by reduced neurotransmitter release. Upregulation of astrocytes and microglia suggests concomitant neuroinflammation, which may further contribute to synaptic damage. However, global synaptic transmission is preserved and memory function remains unaffected in LRP6-Val knock-in mice up to 14 months of age, possibly due to a homeostatic adjustment of synapse density. Synaptic defects caused by LRP6-Val may exacerbate synapse vulnerability to further toxic insults with advancing age, increasing the risk of a pathological transition towards AD. The results of this study advance our understanding of the role of LRP6-mediated Wnt signalling for synapse maintenance during ageing and strengthen the link between aberrant Wnt signalling, synaptic degeneration and Alzheimer's disease

Mechanisms of Experience-dependent Prevention of Plasticity in Visual Circuits

Development of brain function is instructed by both genetically-determined processes (nature) and environmental stimuli (nurture). The relative importance of nature and nurture is a major question in developmental neurobiology. In this dissertation, I investigated the role of visual experience in the development and plasticity of the visual pathway. Each neuron that receives visual input responds to a specific area of the visual field- their receptive field (RF). Developmental refinement reduces RF size and underlies visual acuity, which is important for survival. By rearing Syrian hamsters (Mesocricetus auratus) in constant darkness (dark rearing, DR) from birth, I investigated the role of visual experience in RF refinement and plasticity. Previous work in this lab has shown that developmental refinement of RFs occurs in the absence of visual experience in the superior colliculus (SC), but that RFs unrefine and thus enlarge in adulthood during chronic DR. Using an in vivo electrophysiological approach, I show that, contrary to a widely held view, visual experience is not necessary for refinement of RFs in primary visual cortex (V1). In both SC and V1, RFs refine by postnatal day (P) 60, but enlarge by P90 with chronic DR. One week of visual experience was sufficient to prevent RF enlargement in SC and V1. How normal sensory experience prevents plasticity in mature circuits is not well understood. Using an in vitro electrophysiological approach, I demonstrated that GABAergic inhibition is reduced in DR SC, which in turn affects short-term (but not long-term) synaptic plasticity. The level of GABABR-mediated short-term synaptic depression (STD) that occurs during high-frequency afferent stimulation, such as occurs during vision, is reduced by DR. Using a computational model of RF size, I propose that, in addition to the effect of reduced inhibition, reduced STD of excitation could contribute to enlarged RFs. This work provides insight into mechanisms of development and plasticity of the nervous system. How plasticity is restricted in mature circuits is of fundamental importance in neuroscience and could instruct therapies to prevent maladaptive plasticity in disease and to enhance recovery of function in adults

An investigation into the neural substrates of virtue to determine the key place of virtues in human moral development

Virtues, as described by Aristotle and Aquinas, are understood as dispositions of character to behave in habitual, specific, positive ways; virtue is a critical requirement for human flourishing. From the perspective of Aristotelian-Thomistic anthropology which offers an integrated vision of the material and the rational in the human person, I seek to identify the neural bases for the development and exercise of moral virtue. First I review current neuroscientific knowledge of the capacity of the brain to structure according to experience, to facilitate behaviours, to regulate emotional responses and support goal election. Then, having identified characteristics of moral virtue in the light of the distinctions between cardinal virtues, I propose neural substrates by mapping neuroscientific knowledge to these characteristics. I then investigate the relationship between virtue, including its neurobiological features, and human flourishing. This process allows a contemporary and evidence-based corroboration for a model of moral development based on growth in virtue as understood by Aristotle and Aquinas, and a demonstration of a biological aptitude and predisposition for the development of virtue. Conclusions are drawn with respect to science, ethics, and parenting