Cortical and Striatal Circuits in Huntington's Disease

Huntington's disease (HD) is a hereditary neurodegenerative disorder that typically manifests in midlife with motor, cognitive, and/or psychiatric symptoms. The disease is caused by a CAG triplet expansion in exon 1 of the huntingtin gene and leads to a severe neurodegeneration in the striatum and cortex. Classical electrophysiological studies in genetic HD mouse models provided important insights into the disbalance of excitatory, inhibitory and neuromodulatory inputs, as well as progressive disconnection between the cortex and striatum. However, the involvement of local cortical and striatal microcircuits still remains largely unexplored. Here we review the progress in understanding HD-related impairments in the cortical and basal ganglia circuits, and outline new opportunities that have opened with the development of modern circuit analysis methods. In particular, in vivo imaging studies in mouse HD models have demonstrated early structural and functional disturbances within the cortical network, and optogenetic manipulations of striatal cell types have started uncovering the causal roles of certain neuronal populations in disease pathogenesis. In addition, the important contribution of astrocytes to HD-related circuit defects has recently been recognized. In parallel, unbiased systems biology studies are providing insights into the possible molecular underpinnings of these functional defects at the level of synaptic signaling and neurotransmitter metabolism. With these approaches, we can now reach a deeper understanding of circuit-based HD mechanisms, which will be crucial for the development of effective and targeted therapeutic strategies

Spatiotemporal Asymmetry of Associative Synaptic Plasticity in Fear Conditioning Pathways

SummaryInput-specific long-term potentiation (LTP) in afferent inputs to the amygdala serves an essential function in the acquisition of fear memory. Factors underlying input specificity of synaptic modifications implicated in information transfer in fear conditioning pathways remain unclear. Here we show that the strength of naive synapses in two auditory inputs converging on a single neuron in the lateral nucleus of the amygdala (LA) is only modified when a postsynaptic action potential closely follows a synaptic response. The stronger inhibitory drive in thalamic pathway, as compared with cortical input, hampers the induction of LTP at thalamo-amygdala synapses, contributing to the spatial specificity of LTP in convergent inputs. These results indicate that spike timing-dependent synaptic plasticity in afferent projections to the LA is both temporarily and spatially asymmetric, thus providing a mechanism for the conditioned stimulus discrimination during fear behavior

Investigation of striatal GABAergic output modulation by glutamatergic input

Maintaining the balance between excitation and inhibition within neural circuits is crucial to healthy brain function. Glutamatergic inputs from the cortex and thalamus onto neurons in the striatum seem to play a central role in the development of goal-directed behaviors, including movement and cognition. However, the exact mechanisms through which glutamatergic inputs modulate striatal neurons’ output are still unknown. In this study, we performed in-depth electrophysiological and morphological assays in primary cultured mouse neurons to investigate the role of glutamatergic innervation in striatal GABAergic transmission. Using a two-neuron microcircuit culture model, in which each neuron forms synaptic connections onto itself (autapses) as well as onto the partner neuron (heterosynapses), we could study the interaction of only two neurons of known identity and tissue origin and assess the synaptic properties of all possible connections. By comparing the release characteristics of striatal GABAergic neurons partnered with either a cortical or thalamic glutamatergic neuron or with another striatal GABAergic neuron, we found that glutamatergic input of both origins enhances GABAergic synaptic transmission. In particular, cortical and thalamic innervation causes an increase in the strength of GABAergic responses on striatal neurons. However, increase in the number of readily releasable GABAergic synaptic vesicles and morphological synapses was only induced by cortical innervation. These alterations were contingent on action potential generation, glutamatergic synaptic transmission and BDNF secretion. As cortico-striatal and thalamo-striatal circuits are involved in several neurological diseases, such as Huntington’s disease and psychiatric disorders, our findings may contribute to better understand the pathophysiology of such diseases.Die Aufrechterhaltung des Gleichgewichts zwischen Erregung und Hemmung in neuronalen Schaltkreisen ist für eine gesunde Gehirnfunktion entscheidend. Kortikale und thalamische glutamaterge Innervation auf Neuronen im Striatum, scheinen eine zentrale Rolle bei der Entwicklung von zielgerichtetem Verhalten zu spielen. Die genauen Mechanismen, durch die glutamatergische Innervationen striatale Neuronen modulieren können, sind jedoch noch unbekannt. In dieser Studie werden detaillierte elektrophysiologische und morphologische Untersuchungen in primär kultivierten Mausneuronen durchgeführt, um die Rolle der glutamatergen Innervation bei der striatalen GABAergen Übertragung zu untersuchen. Mit Hilfe eines Zwei-Neuronen-Zellkulturmodells, bei dem jedes Neuron synaptische Verbindungen sowohl zu sich selbst (Autapsen) als auch zu einem Partner-Neuron (Heterosynapsen) eingeht, wurden die Beziehungen von nur zwei Neuronen mit bekannter Identität und Gewebsursprung untersucht, und die synaptische Eigenschaften aller auftretenden Verbindungen bewertet. Der Vergleich der Neurotransmitter Freisetzungseigenschaften von striatalen GABAergen Neuronen, die sich entweder mit einem kortikalen oder thalamischen glutamatergen Neuron oder mit einem anderen striatalen GABAergen Neuron entwickelt haben, zeigte, dass der glutamaterge Eingang beider Ursprünge die GABAerge synaptische Übertragung verbessert. Insbesondere die kortikale und thalamische Innervation bewirkt eine Erhöhung der Stärke der GABAergen Reaktion auf striatale Neuronen. Die Zunahme der Anzahl der leicht freisetzbaren GABAergen synaptischen Vesikel und der Anzahl von morphologischen Synapsen wurde jedoch nur durch kortikale Innervation induziert. Diese Änderungen waren abhängig von der Erzeugung des Aktionspotenzials, der glutamatergen synaptischen Übertragung und der BDNF-Sekretion. Da kortiko-striatale und thalamo-striatale Kreisläufe an mehreren neurologischen Erkrankungen wie Huntington-Krankheit und psychiatrischen Erkrankungen beteiligt sind, können unsere Erkenntnisse dazu beitragen, die Pathophysiologie solcher Erkrankungen besser zu verstehen

Memory consolidation in the cerebellar cortex

Several forms of learning, including classical conditioning of the eyeblink, depend upon the cerebellum. In examining mechanisms of eyeblink conditioning in rabbits, reversible inactivations of the control circuitry have begun to dissociate aspects of cerebellar cortical and nuclear function in memory consolidation. It was previously shown that post-training cerebellar cortical, but not nuclear, inactivations with the GABA(A) agonist muscimol prevented consolidation but these findings left open the question as to how final memory storage was partitioned across cortical and nuclear levels. Memory consolidation might be essentially cortical and directly disturbed by actions of the muscimol, or it might be nuclear, and sensitive to the raised excitability of the nuclear neurons following the loss of cortical inhibition. To resolve this question, we simultaneously inactivated cerebellar cortical lobule HVI and the anterior interpositus nucleus of rabbits during the post-training period, so protecting the nuclei from disinhibitory effects of cortical inactivation. Consolidation was impaired by these simultaneous inactivations. Because direct application of muscimol to the nuclei alone has no impact upon consolidation, we can conclude that post-training, consolidation processes and memory storage for eyeblink conditioning have critical cerebellar cortical components. The findings are consistent with a recent model that suggests the distribution of learning-related plasticity across cortical and nuclear levels is task-dependent. There can be transfer to nuclear or brainstem levels for control of high-frequency responses but learning with lower frequency response components, such as in eyeblink conditioning, remains mainly dependent upon cortical memory storage

Simulating Effects of Learning and Lesions with a Model of Intrinsic and Synaptically Gated Responses of Striatal Cholinergic Interneurons

The giant cholinergic interneurons of the striatum are tonically active neurons (TANs) that respond with characteristic pauses to novel events and to appetitive and aversive conditioned stimuli. Fluctuations in acetylcholine release by TANs modulate performance- and learning-related dynamics in the striatum. Whereas tonic activity emerges from intrinsic properties of these neurons, glutamatergic inputs from thalamic centromedian-parafascicular nuclei, and dopaminergic inputs from midbrain, are required for the generation of pause responses. No prior computational models encompass both intrinsic and synaptically-gated dynamics. We present a mathematical model that robustly accounts for behavior-related electrophysiological properties of TANs in terms of their intrinsic physiological properties and known afferents. In the model, balanced intrinsic hyperpolarizing and depolarizing currents engender tonic firing, and glutamatergic inputs from thalamus (and cortex) both directly excite and indirectly inhibit TANs. If the latter inhibition, presumably mediated by GABAergic interneurons, exceeds a threshold, its effect is amplified by a KIR current to generate a prolonged pause. In the model, the intrinsic mechanisms and external inputs are both modulated by learning-dependent dopamine (DA) signals and our simulations revealed that many learning-dependent behaviors of TANs are explicable without recourse to learning-dependent changes in synapses onto TANs. The "teaching signal" that modulates reinforcement learning at cortico-striatal synapses may be a sequence composed of an adaptively scaled DA burst, a brief ACh burst, and a scaled ACh pause. Such an interpretation is consistent with recent data on cholinergic control of LTD of cortical synapses onto striatal spiny projection neurons.National Science Foundation (SBE-354378); Higher Education Council of Turkey; Canakkale Onsekiz Mart University of Turke

Significance of Input Correlations in Striatal Function

The striatum is the main input station of the basal ganglia and is strongly associated with motor and cognitive functions. Anatomical evidence suggests that individual striatal neurons are unlikely to share their inputs from the cortex. Using a biologically realistic large-scale network model of striatum and cortico-striatal projections, we provide a functional interpretation of the special anatomical structure of these projections. Specifically, we show that weak pairwise correlation within the pool of inputs to individual striatal neurons enhances the saliency of signal representation in the striatum. By contrast, correlations among the input pools of different striatal neurons render the signal representation less distinct from background activity. We suggest that for the network architecture of the striatum, there is a preferred cortico-striatal input configuration for optimal signal representation. It is further enhanced by the low-rate asynchronous background activity in striatum, supported by the balance between feedforward and feedback inhibitions in the striatal network. Thus, an appropriate combination of rates and correlations in the striatal input sets the stage for action selection presumably implemented in the basal ganglia

Parallel Driving and Modulatory Pathways Link the Prefrontal Cortex and Thalamus

Pathways linking the thalamus and cortex mediate our daily shifts from states of attention to quiet rest, or sleep, yet little is known about their architecture in high-order neural systems associated with cognition, emotion and action. We provide novel evidence for neurochemical and synaptic specificity of two complementary circuits linking one such system, the prefrontal cortex with the ventral anterior thalamic nucleus in primates. One circuit originated from the neurochemical group of parvalbumin-positive thalamic neurons and projected focally through large terminals to the middle cortical layers, resembling ‘drivers’ in sensory pathways. Parvalbumin thalamic neurons, in turn, were innervated by small ‘modulatory’ type cortical terminals, forming asymmetric (presumed excitatory) synapses at thalamic sites enriched with the specialized metabotropic glutamate receptors. A second circuit had a complementary organization: it originated from the neurochemical group of calbindin-positive thalamic neurons and terminated through small ‘modulatory’ terminals over long distances in the superficial prefrontal layers. Calbindin thalamic neurons, in turn, were innervated by prefrontal axons through small and large terminals that formed asymmetric synapses preferentially at sites with ionotropic glutamate receptors, consistent with a driving pathway. The largely parallel thalamo-cortical pathways terminated among distinct and laminar-specific neurochemical classes of inhibitory neurons that differ markedly in inhibitory control. The balance of activation of these parallel circuits that link a high-order association cortex with the thalamus may allow shifts to different states of consciousness, in processes that are disrupted in psychiatric diseases

Cortex, countercurrent context, and dimensional integration of lifetime memory

The correlation between relative neocortex size and longevity in mammals encourages a search for a cortical function specifically related to the life-span. A candidate in the domain of permanent and cumulative memory storage is proposed and explored in relation to basic aspects of cortical organization. The pattern of cortico-cortical connectivity between functionally specialized areas and the laminar organization of that connectivity converges on a globally coherent representational space in which contextual embedding of information emerges as an obligatory feature of cortical function. This brings a powerful mode of inductive knowledge within reach of mammalian adaptations, a mode which combines item specificity with classificatory generality. Its neural implementation is proposed to depend on an obligatory interaction between the oppositely directed feedforward and feedback currents of cortical activity, in countercurrent fashion. Direct interaction of the two streams along their cortex-wide local interface supports a scheme of "contextual capture" for information storage responsible for the lifelong cumulative growth of a uniquely cortical form of memory termed "personal history." This approach to cortical function helps elucidate key features of cortical organization as well as cognitive aspects of mammalian life history strategies