Anti-Hebbian plasticity drives sequence learning in striatum.

Spatio-temporal activity patterns have been observed in a variety of brain areas in spontaneous activity, prior to or during action, or in response to stimuli. Biological mechanisms endowing neurons with the ability to distinguish between different sequences remain largely unknown. Learning sequences of spikes raises multiple challenges, such as maintaining in memory spike history and discriminating partially overlapping sequences. Here, we show that anti-Hebbian spike-timing dependent plasticity (STDP), as observed at cortico-striatal synapses, can naturally lead to learning spike sequences. We design a spiking model of the striatal output neuron receiving spike patterns defined as sequential input from a fixed set of cortical neurons. We use a simple synaptic plasticity rule that combines anti-Hebbian STDP and non-associative potentiation for a subset of the presented patterns called rewarded patterns. We study the ability of striatal output neurons to discriminate rewarded from non-rewarded patterns by firing only after the presentation of a rewarded pattern. In particular, we show that two biological properties of striatal networks, spiking latency and collateral inhibition, contribute to an increase in accuracy, by allowing a better discrimination of partially overlapping sequences. These results suggest that anti-Hebbian STDP may serve as a biological substrate for learning sequences of spikes.

Synaptic plasticity through a naturalistic lens.

From the myriad of studies on neuronal plasticity, investigating its underlying molecular mechanisms up to its behavioral relevance, a very complex landscape has emerged. Recent efforts have been achieved toward more naturalistic investigations as an attempt to better capture the synaptic plasticity underpinning of learning and memory, which has been fostered by the development of in vivo electrophysiological and imaging tools. In this review, we examine these naturalistic investigations, by devoting a first part to synaptic plasticity rules issued from naturalistic in vivo-like activity patterns. We next give an overview of the novel tools, which enable an increased spatio-temporal specificity for detecting and manipulating plasticity expressed at individual spines up to neuronal circuit level during behavior. Finally, we put particular emphasis on works considering brain-body communication loops and macroscale contributors to synaptic plasticity, such as body internal states and brain energy metabolism.

Rhythmic oscillations in the midbrain dopaminergic nuclei in mice.

Introduction: Dopamine release in the forebrain by midbrain ventral tegmental nucleus (VTA) and substantia nigra pars compacta (SNc) neurons is implicated in reward processing, goal-directed learning, and decision-making. Rhythmic oscillations of neural excitability underlie coordination of network processing, and have been reported in these dopaminergic nuclei at several frequency bands. This paper provides a comparative characterization of several frequencies of oscillations of local field potential and single unit activity, highlighting some behavioral correlates. Methods: We recorded from optogenetically identified dopaminergic sites in four mice training in operant olfactory and visual discrimination tasks. Results: Rayleigh and Pairwise Phase Consistency (PPC) analyses revealed some VTA/SNc neurons phase-locked to each frequency range, with fast spiking interneurons (FSIs) prevalent at 1-2.5 Hz (slow) and 4 Hz bands, and dopaminergic neurons predominant in the theta band. More FSIs than dopaminergic neurons were phase-locked in the slow and 4 Hz bands during many task events. The highest incidence of phase-locking in neurons was in the slow and 4 Hz bands, and occurred during the delay between the operant choice and trial outcome (reward or punishment) signals. Discussion: These data provide a basis for further examination of rhythmic coordination of activity of dopaminergic nuclei with other brain structures, and its impact for adaptive behavior.

Huntingtin recruits KIF1A to transport synaptic vesicle precursors along the mouse axon to support synaptic transmission and motor skill learning.

Neurotransmitters are released at synapses by synaptic vesicles (SVs), which originate from SV precursors (SVPs) that have traveled along the axon. Because each synapse maintains a pool of SVs, only a small fraction of which are released, it has been thought that axonal transport of SVPs does not affect synaptic function. Here, studying the corticostriatal network both in microfluidic devices and in mice, we find that phosphorylation of the Huntingtin protein (HTT) increases axonal transport of SVPs and synaptic glutamate release by recruiting the kinesin motor KIF1A. In mice, constitutive HTT phosphorylation causes SV over-accumulation at synapses, increases the probability of SV release, and impairs motor skill learning on the rotating rod. Silencing KIF1A in these mice restored SV transport and motor skill learning to wild-type levels. Axonal SVP transport within the corticostriatal network thus influences synaptic plasticity and motor skill learning.

Lactate supply overtakes glucose when neural computational and cognitive loads scale up.

Neural computational power is determined by neuroenergetics, but how and which energy substrates are allocated to various forms of memory engram is unclear. To solve this question, we asked whether neuronal fueling by glucose or lactate scales differently upon increasing neural computation and cognitive loads. Here, using electrophysiology, two-photon imaging, cognitive tasks, and mathematical modeling, we show that both glucose and lactate are involved in engram formation, with lactate supporting long-term synaptic plasticity evoked by high-stimulation load activity patterns and high attentional load in cognitive tasks and glucose being sufficient for less demanding neural computation and learning tasks. Indeed, we show that lactate is mandatory for demanding neural computation, such as theta-burst stimulation, while glucose is sufficient for lighter forms of activity-dependent long-term potentiation (LTP), such as spike timing-dependent plasticity (STDP). We find that subtle variations of spike number or frequency in STDP are sufficient to shift the on-demand fueling from glucose to lactate. Finally, we demonstrate that lactate is necessary for a cognitive task requiring high attentional load, such as the object-in-place task, and for the corresponding in vivo hippocampal LTP expression but is not needed for a less demanding task, such as a simple novel object recognition. Overall, these results demonstrate that glucose and lactate metabolism are differentially engaged in neuronal fueling depending on the complexity of the activity-dependent plasticity and behavior.

Video-Based Automated Assessment of Movement Parameters Consistent with MDS-UPDRS III in Parkinson's Disease.

BACKGROUND: Among motor symptoms of Parkinson's disease (PD), including rigidity and resting tremor, bradykinesia is a mandatory feature to define the parkinsonian syndrome. MDS-UPDRS III is the worldwide reference scale to evaluate the parkinsonian motor impairment, especially bradykinesia. However, MDS-UPDRS III is an agent-based score making reproducible measurements and follow-up challenging. OBJECTIVE: Using a deep learning approach, we developed a tool to compute an objective score of bradykinesia based on the guidelines of the gold-standard MDS-UPDRS III. METHODS: We adapted and applied two deep learning algorithms to detect a two-dimensional (2D) skeleton of the hand composed of 21 predefined points, and transposed it into a three-dimensional (3D) skeleton for a large database of videos of parkinsonian patients performing MDS-UPDRS III protocols acquired in the Movement Disorder unit of Avicenne University Hospital. RESULTS: We developed a 2D and 3D automated analysis tool to study the evolution of several key parameters during the protocol repetitions of the MDS-UPDRS III. Scores from 2D automated analysis showed a significant correlation with gold-standard ratings of MDS-UPDRS III, measured with coefficients of determination for the tapping (0.609) and hand movements (0.701) protocols using decision tree algorithms. The individual correlations of the different parameters measured with MDS-UPDRS III scores carry meaningful information and are consistent with MDS-UPDRS III guidelines. CONCLUSION: We developed a deep learning-based tool to precisely analyze movement parameters allowing to reliably score bradykinesia for parkinsonian patients in a MDS-UPDRS manner.

Cerebellar stimulation prevents Levodopa-induced dyskinesia in mice and normalizes activity in a motor network.

Chronic Levodopa therapy, the gold-standard treatment for Parkinson's Disease (PD), leads to the emergence of involuntary movements, called levodopa-induced dyskinesia (LID). Cerebellar stimulation has been shown to decrease LID severity in PD patients. Here, in order to determine how cerebellar stimulation induces LID alleviation, we performed daily short trains of optogenetic stimulations of Purkinje cells (PC) in freely moving LID mice. We demonstrated that these stimulations are sufficient to suppress LID or even prevent their development. This symptomatic relief is accompanied by the normalization of aberrant neuronal discharge in the cerebellar nuclei, the motor cortex and the parafascicular thalamus. Inhibition of the cerebello-parafascicular pathway counteracted the beneficial effects of cerebellar stimulation. Moreover, cerebellar stimulation reversed plasticity in D1 striatal neurons and normalized the overexpression of FosB, a transcription factor causally linked to LID. These findings demonstrate LID alleviation and prevention by daily PC stimulations, which restore the function of a wide motor network, and may be valuable for LID treatment.

Striatum expresses region-specific plasticity consistent with distinct memory abilities.

The striatum mediates two learning modalities: goal-directed behavior in dorsomedial (DMS) and habits in dorsolateral (DLS) striata. The synaptic bases of these learnings are still elusive. Indeed, while ample research has described DLS plasticity, little remains known about DMS plasticity and its involvement in procedural learning. Here, we find symmetric and asymmetric anti-Hebbian spike-timing-dependent plasticity (STDP) in DMS and DLS, respectively, with opposite plasticity dominance upon increasing corticostriatal activity. During motor-skill learning, plasticity is engaged in DMS and striatonigral DLS neurons only during early learning stages, whereas striatopallidal DLS neurons are mobilized only during late phases. With a mathematical modeling approach, we find that symmetric anti-Hebbian STDP favors memory flexibility, while asymmetric anti-Hebbian STDP favors memory maintenance, consistent with memory processes at play in procedural learning.

Extracellular and intracellular components of the impedance of neural tissue.

Electric phenomena in brain tissue can be measured using extracellular potentials, such as the local field potential, or the electro-encephalogram. The interpretation of these signals depends on the electric structure and properties of extracellular media, but the measurements of these electric properties are still debated. Some measurements point to a model in which the extracellular medium is purely resistive, and thus parameters such as electric conductivity and permittivity should be independent of frequency. Other measurements point to a pronounced frequency dependence of these parameters, with scaling laws that are consistent with capacitive or diffusive effects. However, these experiments correspond to different preparations, and it is unclear how to correctly compare them. Here, we provide for the first time, impedance measurements (in the 1-10 kHz frequency range) using the same setup in various preparations, from primary cell cultures to acute brain slices, and a comparison with similar measurements performed in artificial cerebrospinal fluid with no biological material. The measurements show that when the current flows across a cell membrane, the frequency dependence of the macroscopic impedance between intracellular and extracellular electrodes is significant, and cannot be captured by a model with resistive media. Fitting a mean-field model to the data shows that this frequency dependence could be explained by the ionic diffusion mainly associated with Debye layers surrounding the membranes. We conclude that neuronal membranes and their ionic environment induce strong deviations to resistivity that should be taken into account to correctly interpret extracellular potentials generated by neurons.

Npas4 regulates medium spiny neuron physiology and gates cocaine-induced hyperlocomotion.

We show here that the transcription factor Npas4 is an important regulator of medium spiny neuron spine density and electrophysiological parameters and that it determines the magnitude of cocaine-induced hyperlocomotion in mice. Npas4 is induced by synaptic stimuli that cause calcium influx, but not dopaminergic or PKA-stimulating input, in mouse medium spiny neurons and human iPSC-derived forebrain organoids. This induction is independent of ubiquitous kinase pathways such as PKA and MAPK cascades, and instead depends on calcineurin and nuclear calcium signalling. Npas4 controls a large regulon containing transcripts for synaptic molecules, such as NMDA receptors and VDCC subunits, and determines in vivo MSN spine density, firing rate, I/O gain function and paired-pulse facilitation. These functions at the molecular and cellular levels control the locomotor response to drugs of abuse, as Npas4 knockdown in the nucleus accumbens decreases hyperlocomotion in response to cocaine in male mice while leaving basal locomotor behaviour unchanged.

Intracellular Properties of Deep-Layer Pyramidal Neurons in Frontal Eye Field of Macaque Monkeys.

Although many details remain unknown, several positive statements can be made about the laminar distribution of primate frontal eye field (FEF) neurons with different physiological properties. Most certainly, pyramidal neurons in the deep layer of FEF that project to the brainstem carry movement and fixation signals but clear evidence also support that at least some deep-layer pyramidal neurons projecting to the superior colliculus carry visual responses. Thus, deep-layer neurons in FEF are functionally heterogeneous. Despite the useful functional distinctions between neuronal responses in vivo, the underlying existence of distinct cell types remain uncertain, mostly due to methodological limitations of extracellular recordings in awake behaving primates. To substantiate the functionally defined cell types encountered in the deep layer of FEF, we measured the biophysical properties of pyramidal neurons recorded intracellularly in brain slices issued from macaque monkey biopsies. Here, we found that biophysical properties recorded in vitro permit us to distinguish two main subtypes of regular-spiking neurons, with, respectively, low-resistance and low excitability vs. high-resistance and strong excitability. These results provide useful constraints for cognitive models of visual attention and saccade production by indicating that at least two distinct populations of deep-layer neurons exist.

Engrams of Fast Learning.

Fast learning designates the behavioral and neuronal mechanisms underlying the acquisition of a long-term memory trace after a unique and brief experience. As such it is opposed to incremental, slower reinforcement or procedural learning requiring repetitive training. This learning process, found in most animal species, exists in a large spectrum of natural behaviors, such as one-shot associative, spatial, or perceptual learning, and is a core principle of human episodic memory. We review here the neuronal and synaptic long-term changes associated with fast learning in mammals and discuss some hypotheses related to their underlying mechanisms. We first describe the variety of behavioral paradigms used to test fast learning memories: those preferentially involve a single and brief (from few hundred milliseconds to few minutes) exposures to salient stimuli, sufficient to trigger a long-lasting memory trace and new adaptive responses. We then focus on neuronal activity patterns observed during fast learning and the emergence of long-term selective responses, before documenting the physiological correlates of fast learning. In the search for the engrams of fast learning, a growing body of evidence highlights long-term changes in gene expression, structural, intrinsic, and synaptic plasticities. Finally, we discuss the potential role of the sparse and bursting nature of neuronal activity observed during the fast learning, especially in the induction plasticity mechanisms leading to the rapid establishment of long-term synaptic modifications. We conclude with more theoretical perspectives on network dynamics that could enable fast learning, with an overview of some theoretical approaches in cognitive neuroscience and artificial intelligence.

Lights on Endocannabinoid-Mediated Synaptic Potentiation.

The endocannabinoid (eCB) system is a lipid-based neurotransmitter complex that plays crucial roles in the neural control of learning and memory. The current model of eCB-mediated retrograde signaling is that eCBs released from postsynaptic elements travel retrogradely to presynaptic axon terminals, where they activate cannabinoid type-1 receptors (CB1Rs) and ultimately decrease neurotransmitter release on a short- or long-term scale. An increasing body of evidence has enlarged this view and shows that eCBs, besides depressing synaptic transmission, are also able to increase neurotransmitter release at multiple synapses of the brain. This indicates that eCBs act as bidirectional regulators of synaptic transmission and plasticity. Recently, studies unveiled links between the expression of eCB-mediated long-term potentiation (eCB-LTP) and learning, and between its dysregulation and several pathologies. In this review article, we first distinguish the various forms of eCB-LTP based on their mechanisms, resulting from homosynaptically or heterosynaptically-mediated processes. Next, we consider the neuromodulation of eCB-LTP, its behavioral impact on learning and memory, and finally, eCB-LTP disruptions in various pathologies and its potential as a therapeutic target in disorders such as stress coping, addiction, Alzheimer's and Parkinson's disease, and pain. Cannabis is gaining popularity as a recreational substance as well as a medicine, and multiple eCB-based drugs are under development. In this context, it is critical to understand eCB-mediated signaling in its multi-faceted complexity. Indeed, the bidirectional nature of eCB-based neuromodulation may offer an important key to interpret the functions of the eCB system and how it is impacted by cannabis and other drugs.

Deep brain stimulation-guided optogenetic rescue of parkinsonian symptoms.

Deep brain stimulation (DBS) of the subthalamic nucleus is a symptomatic treatment of Parkinson's disease but benefits only to a minority of patients due to stringent eligibility criteria. To investigate new targets for less invasive therapies, we aimed at elucidating key mechanisms supporting deep brain stimulation efficiency. Here, using in vivo electrophysiology, optogenetics, behavioral tasks and mathematical modeling, we found that subthalamic stimulation normalizes pathological hyperactivity of motor cortex pyramidal cells, while concurrently activating somatostatin and inhibiting parvalbumin interneurons. In vivo opto-activation of cortical somatostatin interneurons alleviates motor symptoms in a parkinsonian mouse model. A computational model highlights that a decrease in pyramidal neuron activity induced by DBS or by a stimulation of cortical somatostatin interneurons can restore information processing capabilities. Overall, these results demonstrate that activation of cortical somatostatin interneurons may constitute a less invasive alternative than subthalamic stimulation.

Concurrent Thalamostriatal and Corticostriatal Spike-Timing-Dependent Plasticity and Heterosynaptic Interactions Shape Striatal Plasticity Map.

The striatum integrates inputs from the cortex and thalamus, which display concomitant or sequential activity. The striatum assists in forming memory, with acquisition of the behavioral repertoire being associated with corticostriatal (CS) plasticity. The literature has mainly focused on that CS plasticity, and little remains known about thalamostriatal (TS) plasticity rules or CS and TS plasticity interactions. We undertook here the study of these plasticity rules. We found bidirectional Hebbian and anti-Hebbian spike-timing-dependent plasticity (STDP) at the thalamic and cortical inputs, respectively, which were driving concurrent changes at the striatal synapses. Moreover, TS- and CS-STDP induced heterosynaptic plasticity. We developed a calcium-based mathematical model of the coupled TS and CS plasticity, and simulations predict complex changes in the CS and TS plasticity maps depending on the precise cortex-thalamus-striatum engram. These predictions were experimentally validated using triplet-based STDP stimulations, which revealed the significant remodeling of the CS-STDP map upon TS activity, which is notably the induction of the LTD areas in the CS-STDP for specific timing regimes. TS-STDP exerts a greater influence on CS plasticity than CS-STDP on TS plasticity. These findings highlight the major impact of precise timing in cortical and thalamic activity for the memory engram of striatal synapses.

Circulating Triglycerides Gate Dopamine-Associated Behaviors through DRD2-Expressing Neurons.

Energy-dense food alters dopaminergic (DA) transmission in the mesocorticolimbic (MCL) system and can promote reward dysfunctions, compulsive feeding, and weight gain. Yet the mechanisms by which nutrients influence the MCL circuitry remain elusive. Here, we show that nutritional triglycerides (TGs), a conserved post-prandial metabolic signature among mammals, can be metabolized within the MCL system and modulate DA-associated behaviors by gating the activity of dopamine receptor subtype 2 (DRD2)-expressing neurons through a mechanism that involves the action of the lipoprotein lipase (LPL). Further, we show that in humans, post-prandial TG excursions modulate brain responses to food cues in individuals carrying a genetic risk for reduced DRD2 signaling. Collectively, these findings unveil a novel mechanism by which dietary TGs directly alter signaling in the reward circuit to regulate behavior, thereby providing a new mechanistic basis by which energy-rich diets may lead to (mal)adaptations in DA signaling that underlie reward deficit and compulsive behavior.

BDNF Controls Bidirectional Endocannabinoid Plasticity at Corticostriatal Synapses.

The dorsal striatum exhibits bidirectional corticostriatal synaptic plasticity, NMDAR and endocannabinoids (eCB) mediated, necessary for the encoding of procedural learning. Therefore, characterizing factors controlling corticostriatal plasticity is of crucial importance. Brain-derived neurotrophic factor (BDNF) and its receptor, the tropomyosine receptor kinase-B (TrkB), shape striatal functions, and their dysfunction deeply affects basal ganglia. BDNF/TrkB signaling controls NMDAR plasticity in various brain structures including the striatum. However, despite cross-talk between BDNF and eCBs, the role of BDNF in eCB plasticity remains unknown. Here, we show that BDNF/TrkB signaling promotes eCB-plasticity (LTD and LTP) induced by rate-based (low-frequency stimulation) or spike-timing-based (spike-timing-dependent plasticity, STDP) paradigm in striatum. We show that TrkB activation is required for the expression and the scaling of both eCB-LTD and eCB-LTP. Using 2-photon imaging of dendritic spines combined with patch-clamp recordings, we show that TrkB activation prolongs intracellular calcium transients, thus increasing eCB synthesis and release. We provide a mathematical model for the dynamics of the signaling pathways involved in corticostriatal plasticity. Finally, we show that TrkB activation enlarges the domain of expression of eCB-STDP. Our results reveal a novel role for BDNF/TrkB signaling in governing eCB-plasticity expression in striatum and thus the engram of procedural learning.

Environmental enrichment shapes striatal spike-timing-dependent plasticity in vivo.

Behavioural experience, such as environmental enrichment (EE), induces long-term effects on learning and memory. Learning can be assessed with the Hebbian paradigm, such as spike-timing-dependent plasticity (STDP), which relies on the timing of neuronal activity on either side of the synapse. Although EE is known to control neuronal excitability and consequently spike timing, whether EE shapes STDP remains unknown. Here, using in vivo long-duration intracellular recordings at the corticostriatal synapses we show that EE promotes asymmetric anti-Hebbian STDP, i.e. spike-timing-dependent-potentiation (tLTP) for post-pre pairings and spike-timing-dependent-depression (tLTD) for pre-post pairings, whereas animals grown in standard housing show mainly tLTD and a high failure rate of plasticity. Indeed, in adult rats grown in standard conditions, we observed unidirectional plasticity (mainly symmetric anti-Hebbian tLTD) within a large temporal window (~200 ms). However, rats grown for two months in EE displayed a bidirectional STDP (tLTP and tLTD depending on spike timing) in a more restricted temporal window (~100 ms) with low failure rate of plasticity. We also found that the effects of EE on STDP characteristics are influenced by the anaesthesia status: the deeper the anaesthesia, the higher the absence of plasticity. These findings establish a central role for EE and the anaesthetic regime in shaping in vivo, a synaptic Hebbian learning rule such as STDP.

CYP46A1 gene therapy deciphers the role of brain cholesterol metabolism in Huntington's disease.

Dysfunctions in brain cholesterol homeostasis have been extensively related to brain disorders. The main pathway for brain cholesterol elimination is its hydroxylation into 24S-hydroxycholesterol by the cholesterol 24-hydrolase, CYP46A1. Increasing evidence suggests that CYP46A1 has a role in the pathogenesis and progression of neurodegenerative disorders, and that increasing its levels in the brain is neuroprotective. However, the mechanisms underlying this neuroprotection remain to be fully understood. Huntington's disease is a fatal autosomal dominant neurodegenerative disease caused by an abnormal CAG expansion in huntingtin's gene. Among the multiple cellular and molecular dysfunctions caused by this mutation, altered brain cholesterol homeostasis has been described in patients and animal models as a critical event in Huntington's disease. Here, we demonstrate that a gene therapy approach based on the delivery of CYP46A1, the rate-limiting enzyme for cholesterol degradation in the brain, has a long-lasting neuroprotective effect in Huntington's disease and counteracts multiple detrimental effects of the mutated huntingtin. In zQ175 Huntington's disease knock-in mice, CYP46A1 prevented neuronal dysfunctions and restored cholesterol homeostasis. These events were associated to a specific striatal transcriptomic signature that compensates for multiple mHTT-induced dysfunctions. We thus explored the mechanisms for these compensations and showed an improvement of synaptic activity and connectivity along with the stimulation of the proteasome and autophagy machineries, which participate to the clearance of mutant huntingtin (mHTT) aggregates. Furthermore, BDNF vesicle axonal transport and TrkB endosome trafficking were restored in a cellular model of Huntington's disease. These results highlight the large-scale beneficial effect of restoring cholesterol homeostasis in neurodegenerative diseases and give new opportunities for developing innovative disease-modifying strategies in Huntington's disease.