Associative Visuomotor Learning Using Transcranial Magnetic Stimulation Induces Stimulus-Response Interference.

Cytokines are constitutively released in the healthy brain by resident myeloid cells to keep proper synaptic plasticity, either in the form of Hebbian synaptic plasticity or of homeostatic plasticity. However, when cytokines dramatically increase, establishing a status of neuroinflammation, the synaptic action of such molecules remarkably interferes with brain circuits of learning and cognition and contributes to excitotoxicity and neurodegeneration. Among others, interleukin-1β (IL-1β) and tumor necrosis factor (TNF) are the best studied proinflammatory cytokines in both physiological and pathological conditions and have been invariably associated with long-term potentiation (LTP) (Hebbian synaptic plasticity) and synaptic scaling (homeostatic plasticity), respectively. Multiple sclerosis (MS) is the prototypical neuroinflammatory disease, in which inflammation triggers excitotoxic mechanisms contributing to neurodegeneration. IL-β and TNF are increased in the brain of MS patients and contribute to induce the changes in synaptic plasticity occurring in MS patients and its animal model, the experimental autoimmune encephalomyelitis (EAE). This review will introduce and discuss current evidence of the role of IL-1β and TNF in the regulation of synaptic strength at both physiological and pathological levels, in particular speculating on their involvement in the synaptic plasticity changes observed in the EAE brain.

Growing evidence supports a critical role for the dorsal striatum in cognitive as well as motor control. Both lesions and <i>in vivo</i> recordings demonstrate a transition in the engaged dorsal striatal subregion, from dorsomedial to dorsolateral, as skill performance shifts from an attentive phase to a more automatic or habitual phase. What are the neural mechanisms supporting the cognitive and behavioral transitions in skill learning? To pursue this question, we used T-maze training during which rats transition from early, attentive (dorsomedial) to late habitual (dorsolateral) performance. Following early or late training, we performed the first direct comparison of bidirectional synaptic plasticity in striatal brain slices, and the first evaluation of striatal synaptic plasticity by hemisphere relative to a learned turn. Consequently, we find that long-term potentiation and long-term depression are independently modulated with learning rather than reciprocally linked as previously suggested. Our results establish that modulation of evoked synaptic plasticity with learning depends on striatal subregion, training stage, and hemisphere relative to the learned turn direction. Exclusive to the contralateral hemisphere, intrinsic excitability is enhanced in dorsomedial relative to dorsolateral medium spiny neurons early in training and population responses are dampened late in training. Neuronal reconstructions indicate dendritic remodeling after training, which may represent a novel form of pruning. In conclusion, we describe region- and hemisphere-specific changes in striatal synaptic, intrinsic, and morphological plasticity which correspond to T-maze learning stages, and which may play a role in the cognitive transition between attentive and habitual strategies. <b>SIGNIFICANCE STATEMENT</b> We investigated neural plasticity in dorsal striatum from rats that were briefly or extensively trained on a directional T-maze task. Our results demonstrate that both the extent of training and the direction a rat learns to turn control the location and type of change in synaptic plasticity. In addition, brief training produces changes in neuron excitability only within one striatal subregion, whereas all training produces widespread changes in dendritic morphology. Our results suggest that activity in dorsomedial striatum strengthens the rewarded turn after brief training, whereas activity in dorsolateral striatum suppresses unrewarded turns after extensive training. This study illuminates how plasticity mediates learning using a task recognized for transitioning subjects from attentive to automatic performance.

Ca(2+) influx through postsynaptic Ca(v)1.x L-type voltage-gated channels (LTCCs) is particularly effective in activating neuronal biochemical signaling pathways that might be involved in Hebbian synaptic plasticity (i.e., long-term potentiation and depression) and learning and memory. Here, we demonstrate that Ca(v)1.2 is the functionally relevant LTCC isoform in the thalamus-amygdala pathway of mice. We further show that acute pharmacological block of LTCCs abolishes Hebbian plasticity in the thalamus-amygdala pathway and impairs the acquisition of conditioned fear. On the other hand, chronic genetic loss of Ca(v)1.2 triggers a homeostatic change of the synapse, leading to a fundamental alteration of the mechanism of Hebbian plasticity by synaptic incorporation of Ca(2+)-permeable, GluA2-lacking AMPA receptors. Our results demonstrate for the first time the importance of the Ca(v)1.2 LTCC subtype in synaptic plasticity and fear memory acquisition.

Spiking neural networks (SNNs) are the basis for many energy-efficient neuromorphic hardware systems. While there has been substantial progress in SNN research, artificial SNNs still lack many capabilities of their biological counterparts. In biological neural systems, memory is a key component that enables the retention of information over a huge range of temporal scales, ranging from hundreds of milliseconds up to years. While Hebbian plasticity is believed to play a pivotal role in biological memory, it has so far been analyzed mostly in the context of pattern completion and unsupervised learning in artificial and SNNs. Here, we propose that Hebbian plasticity is fundamental for computations in biological and artificial spiking neural systems. We introduce a novel memory-augmented SNN architecture that is enriched by Hebbian synaptic plasticity. We show that Hebbian enrichment renders SNNs surprisingly versatile in terms of their computational as well as learning capabilities. It improves their abilities for out-of-distribution generalization, one-shot learning, cross-modal generative association, language processing, and reward-based learning. This suggests that powerful cognitive neuromorphic systems can be built based on this principle.

Hebbian and homeostatic synaptic plasticity of AMPA receptors in epileptogenesis

Interval Timing in Aversive Conditioning: Neural Correlates in Amygdala and Related Networks in Rats

Age-dependent changes in brain hydration and synaptic plasticity

Ovariectomy-induced disruption of long-term synaptic depression in the hippocampal CA1 region in vivo is attenuated with chronic estrogen replacement

1. In a previous study, using a chronic cat preparation subjected to an associative conditioning procedure, we described the plasticity of the thalamo-cortical pathway by qualitatively and quantitatively analyzing the motor responses induced by stimulating each of the relays on the cerebello-thalamo-cortical pathway. In the present study, it was proposed to analyze the effects on the synapses located between thalamic endings and cortical neurones, using a twofold behavioral and electrophysiological approach, with a view to correlating the patterns of synaptic plasticity with the changes in the motor responses recorded. 2. For this purpose, a reduced, functionally organized sensorimotor circuit, which can be taken to be a neuronal analog of associative conditioning, was studied in an awake chronic animal preparation. This circuit was defined on the basis of the sites at which conditioned (CS) and unconditioned stimuli (UCS) were applied: the CS was applied at a site on the cerebellar interpositus nucleus which activated the forepaw musculature so as to induce flexion movements and the UCS was applied to the skin of the distal part of that paw so as to induce reflex flexion movements. By repetitively activating the central nervous pathways by the associated CS and UCS according to a predefined temporal pattern, the efficiency of the thalamo-cortical pathway's contribution to the movement production was enhanced, and its capacity to convey the cerebellar inputs to neurons in the motor cortex increased. 3. The associative nature of the conditioning was tested using previously established criteria. The setting up of motor and central changes in response to the repetitive presentation of paired CS and UCS, the fact that these changes were reversible because they could be abolished by applying extinction procedures, and the consistency of their occurrence whenever the CS was applied repeatedly alone for several days to naive animals, all showed that the stimuli of both kinds (CS and UCS) had to be applied together for the plasticity of the thalamo-cortical pathway to be expressed. 4. By determining whether the waves constituting the cerebello-cortical responses were excitatory or inhibitory, the nature of the changes in the transmission of the cerebellar impulses to neurons in the motor cortex was established.(ABSTRACT TRUNCATED AT 400 WORDS)

Various hippocampal and neocortical synapses of mammalian brain show both short-term plasticity and long-term plasticity, which are considered to underlie learning and memory by the brain. According to Hebb’s postulate, synaptic plasticity encodes memory traces of past experiences into cell assemblies in cortical circuits. However, it remains unclear how the various forms of long-term and short-term synaptic plasticity cooperatively create and reorganize such cell assemblies. Here, we investigate the mechanism in which the three forms of synaptic plasticity known in cortical circuits, i.e., spike-timing-dependent plasticity (STDP), short-term depression (STD) and homeostatic plasticity, cooperatively generate, retain and reorganize cell assemblies in a recurrent neuronal network model. We show that multiple cell assemblies generated by external stimuli can survive noisy spontaneous network activity for an adequate range of the strength of STD. Furthermore, our model predicts that a symmetric temporal window of STDP, such as observed in dopaminergic modulations on hippocampal neurons, is crucial for the retention and integration of multiple cell assemblies. These results may have implications for the understanding of cortical memory processes.

Complex Adaptations to Traumatic Stress: From Neurobiological to Social and Cultural Aspects

A problem with Hebb and local spikes

Learning or the formation of memories is a key component of biological intelligence. One distinguishes between different types of memory as, for instance, the declarative memory denoting the storage of facts and concepts which are extracted from perceived stimuli. Thereby, an important question is how the brain distinguishes between stimuli that should be associated and those to be discriminated. Investigating this mechanism, in psychophysical experiments, rats were exposed to gradually morphed environments while recording activity in hippocampal place cells [1,2]. Stability of the recorded place-dependent activation patterns was dependent on the order in which the different environments were explored. In other words, stimulus discrimination or association depends on the order of presentation. Theoretical models of memory rely on the hypothesis that memorization is implemented through activity-dependent synaptic plasticity. Environmental patterns are reflected by correlated activity in subgroups of neurons leading to high recurrent synaptic efficacies among them. These groups of highly interconnected neurons are named cell assemblies (CAs). This long-standing concept with its basic ability of pattern completion is a promising approach to explain several cognitive phenomena [3]. Combining the theory of CAs with the principle of self-organizing maps (SOMs) [4], we present a biologically plausible network model able to reproduce the upper experimental findings. Basically our model consists of three populations of neurons. An input population projects through random excitatory connections on a recurrent layer. Neurons within the layer interact by excitatory synapses. Competition is introduced by an inhibitory population mutually interconnected with every layer neuron. For all neurons, we use a rate-coded neuron model with sigmoidal transfer functions. The plasticity model combines (Hebbian) synaptic plasticity and synaptic scaling (SPASS) [5]. Stimuli are inserted as activity patterns in the input population passing them on via afferent plastic synapses. Recurrent lateral connections in the layer reach a circular neighborhood of fixed range and are also plastic. The incoming excitatory synapses the inhibitory population receives as well as its outgoing connections are non-plastic. In agreement with SOM, our concept maps sufficiently differing stimuli to different representations (CAs) in the layer. Comparable to the experimental procedures described above, we define two non-overlapping activity patterns A and B. According with [1], first we transform stimulus A gradually into B with a short pause between each step of the transition sequence. After A lead to the formation of one memory representation, or rather a single CA, this CA is maintained throughout the following learning protocol. Secondly, the protocol of [2] demands a random presentation of the transition patterns. In this case, we observe the formation of multiple representations. Thus, our model reproduces the experimental findings described above. In contrast to existing theoretical studies [6], it does not require stimulus-dependent modifications of the plasticity rule itself. It further allows for investigating the influence of different variations in the learning protocol as, for instance, of the stimulus presentation time.

Effects of conditioned stimulus presentation on diminution of the unconditioned response in aversive classical conditioning

Opportunities for the treatment of Parkinson’s disease (PD) by cortical stimulation are open. This review outlines the main arguments for the use of cortical stimulation in PD: the widespread cortical dysfunction that could be corrected by cortical stimulation; the main mechanism of action of subthalamic nucleus stimulation that could take place within the primary motor cortex; and the ability of cortical stimulation to modulate basal ganglia activity by exciting cortico–basal ganglia projections. Such neuromodulatory effects could correspond to either stimulus-locked changes in brain rhythms or delayed changes in synaptic plasticity. Repetitive transcranial magnetic stimulation can produce transient improvement of motor performance when the primary motor cortex or the supplementary motor area is targeted. Alleviation of mood and cognitive disorders are rather observed when repetitive transcranial magnetic stimulation is applied to the dorsolateral prefrontal cortex. However, to produce more permanent therapeutic effects, chronic stimulation using surgically implanted electrodes is necessary. For this purpose, epidural implantation is safer and should be used in preference to subdural implantation. Pioneering results of epidural motor cortex stimulation in PD have been published, but they relate to case reports and open studies, precluding any definitive conclusion. Epidural cortical stimulation is easy to perform and could be a valuable therapeutic alternative to deep-brain stimulation. However, new epidural leads need to be designed before considering the development of such a technique for PD treatment.