Pre-clinical evidence that methylphenidate increases motivation and/or reward preference to search for high value rewards.

Methylphenidate is a stimulant used to treat attention deficit and hyperactivity disorder (ADHD). In the last decade, illicit use of methylphenidate has increased among healthy young adults, who consume the drug under the assumption that it will improve cognitive performance. However, the studies that aimed to assess the methylphenidate effects on memory are not consistent. Here, we tested whether the effect of methylphenidate on a spatial memory task can be explained as a motivational and/or a reward effect. We tested the effects of acute and chronic i.p. administration of 0.3, 1 or 3 mg/kg of methylphenidate on motivation, learning and memory by using the 8-arm radial maze task. Adult male Wistar rats learned that 3 of the 8 arms of the maze were consistently baited with 1, 3, or 6 sucrose pellets, and the number of entries and reentries into reinforced and non-reinforced arms of the maze were scored. Neither acute nor chronic (20 days) methylphenidate treatment affected the number of entries in the non-baited arms. However, chronic, but not acute, 1-3 mg/kg methylphenidate increased the number of reentries in the higher reward arms, which suggests a motivational/rewarding effect rather than a working memory deficit. In agreement with this hypothesis, the methylphenidate treatment also decreased the approach latency to the higher reward arms, increased the approach latency to the low reward arm, and increased the time spent in the high, but not low, reward arm. These findings suggest that methylphenidate may act more as a motivational enhancer rather than a cognitive enhancer in healthy people.

Corrigendum: The Energy Homeostasis Principle: Neuronal Energy Regulation Drives Local Network Dynamics Generating Behavior.

[This corrects the article DOI: 10.3389/fncom.2019.00049.].

Basal ganglia oscillations as biomarkers for targeting circuit dysfunction in Parkinson's disease.

Oscillations are a naturally occurring phenomenon in highly interconnected dynamical systems. However, it is thought that excessive synchronized oscillations in brain circuits can be detrimental for many brain functions by disrupting neuronal information processing. Because synchronized basal ganglia oscillations are a hallmark of Parkinson's disease (PD), it has been suggested that aberrant rhythmic activity associated with symptoms of the disease could be used as a physiological biomarker to guide pharmacological and electrical neuromodulatory interventions. We here briefly review the various manifestations of basal ganglia oscillations observed in human subjects and in animal models of PD. In this context, we also review the evidence supporting a pathophysiological role of different oscillations for the suppression of voluntary movements as well as for the induction of excessive motor activity. In light of these findings, it is discussed how oscillations could be used to guide a more precise targeting of dysfunctional circuits to obtain improved symptomatic treatment of PD.

The Energy Homeostasis Principle: Neuronal Energy Regulation Drives Local Network Dynamics Generating Behavior.

A major goal of neuroscience is understanding how neurons arrange themselves into neural networks that result in behavior. Most theoretical and experimental efforts have focused on a top-down approach which seeks to identify neuronal correlates of behaviors. This has been accomplished by effectively mapping specific behaviors to distinct neural patterns, or by creating computational models that produce a desired behavioral outcome. Nonetheless, these approaches have only implicitly considered the fact that neural tissue, like any other physical system, is subjected to several restrictions and boundaries of operations. Here, we proposed a new, bottom-up conceptual paradigm: The Energy Homeostasis Principle, where the balance between energy income, expenditure, and availability are the key parameters in determining the dynamics of neuronal phenomena found from molecular to behavioral levels. Neurons display high energy consumption relative to other cells, with metabolic consumption of the brain representing 20% of the whole-body oxygen uptake, contrasting with this organ representing only 2% of the body weight. Also, neurons have specialized surrounding tissue providing the necessary energy which, in the case of the brain, is provided by astrocytes. Moreover, and unlike other cell types with high energy demands such as muscle cells, neurons have strict aerobic metabolism. These facts indicate that neurons are highly sensitive to energy limitations, with Gibb's free energy dictating the direction of all cellular metabolic processes. From this activity, the largest energy, by far, is expended by action potentials and post-synaptic potentials; therefore, plasticity can be reinterpreted in terms of their energy context. Consequently, neurons, through their synapses, impose energy demands over post-synaptic neurons in a close loop-manner, modulating the dynamics of local circuits. Subsequently, the energy dynamics end up impacting the homeostatic mechanisms of neuronal networks. Furthermore, local energy management also emerges as a neural population property, where most of the energy expenses are triggered by sensory or other modulatory inputs. Local energy management in neurons may be sufficient to explain the emergence of behavior, enabling the assessment of which properties arise in neural circuits and how. Essentially, the proposal of the Energy Homeostasis Principle is also readily testable for simple neuronal networks.

Oscillations in cortico-basal ganglia circuits: implications for Parkinson's disease and other neurologic and psychiatric conditions.

Cortico-basal ganglia circuits are thought to play a crucial role in the selection and control of motor behaviors and have also been implicated in the processing of motivational content and in higher cognitive functions. During the last two decades, electrophysiological recordings in basal ganglia circuits have shown that several disease conditions are associated with specific changes in the temporal patterns of neuronal activity. In particular, synchronized oscillations have been a frequent finding suggesting that excessive synchronization of neuronal activity may be a pathophysiological mechanism involved in a wide range of neurologic and psychiatric conditions. We here review the experimental support for this hypothesis primarily in relation to Parkinson's disease but also in relation to dystonia, essential tremor, epilepsy, and psychosis/schizophrenia.

Motor deficits and beta oscillations are dissociable in an alpha-synuclein model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterised by progressive motor symptoms resulting from chronic loss of dopaminergic neurons in the nigrostriatal pathway. The over expression of the protein alpha-synuclein in the substantia nigra has been used to induce progressive dopaminergic neuronal loss and to reproduce key histopathological and temporal features of PD in animal models. However, the neurophysiological aspects of the alpha-synuclein PD model have been poorly characterised. Hereby, we performed chronic in vivo electrophysiological recordings in the corticostriatal circuit of rats injected with viral vector to over express alpha-synuclein in the right substantia nigra. Our model, previously shown to exhibit mild motor deficits, presented moderate dopaminergic cell loss but did not present prominent local field potential oscillations in the beta frequency range (11-30 Hz), considered a hallmark of PD, during the 9 weeks after onset of alpha-synuclein over expression. Spinal cord stimulation, a potential PD symptomatic therapy, was applied regularly from sixth to ninth week after alpha-synuclein over expression onset and had an inhibitory effect on the firing rate of corticostriatal neurons in both control and alpha-synuclein hemispheres. Dopamine synthesis inhibition at the end of the experiment resulted in severe parkinsonian symptoms such as akinesia and increased beta and high-frequency (>90 Hz) oscillations. These results suggest that the alpha-synuclein PD model with moderate level of dopaminergic depletion does not reproduce the prominent corticostriatal beta oscillatory activity associated to parkinsonian conditions.

Spinal cord stimulation improves forelimb use in an alpha-synuclein animal model of Parkinson's disease.

Neuromodulation by spinal cord stimulation has been proposed as a symptomatic treatment for Parkinson's disease. We tested the chronic effects of spinal cord stimulation in a progressive model of Parkinson's based on overexpression of alpha-synuclein in the substantia nigra. Adult Sprague Dawley rats received unilateral injections of adeno-associated virus serotype 6 (AAV6) in the substantia nigra to express alpha-synuclein. Locomotion and forepaw use of the rats were evaluated during the next 10 weeks. Starting on week 6, a group of AAV6-injected rats received spinal cord stimulation once a week. At the end of the experiment, tyrosine hydroxylase and alpha-synuclein immunostaining were performed. Rats with unilateral alpha-synuclein expression showed a significant decrease in the use of the contralateral forepaw, which was mildly but significantly reverted by spinal cord stimulation applied once a week from the 6th to the 10th week after the AAV6 injection. Long-term spinal cord stimulation proved to be effective to suppress or delay motor symptoms in a sustained and progressive model of Parkinson's and might become an alternative, less invasive neuromodulation option to treat this disease.

Estimulación de la médula espinal: una nueva estrategia terapéutica para restaurar la función motora / Spinal cord stimulation: a new therapeutic strategy to restore motor function

La estimulación de la Médula Espinal (EME) es una técnica de neuromodulación que ha mostrado ser efectiva en el manejo de los trastornos motores propios de enfermedades tan devastadoras como la Enfermedad de Parkinson (EP) y las lesiones de la médula espinal. Considerando que ambas patologías cuentan con opciones terapéuticas limitadas, la EME se podría posicionar como una técnica prometedora. Los mecanismos por los cuales operaría la estimulación difieren en ambos casos, generando cambios en la circuitería espinal local en el caso de las lesiones medulares, y cambios supraespinales, en el caso de la EP. En esta revisión se busca analizar los efectos de la EME en ambas enfermedades, tanto en modelos animales como en pacientes, hacer una breve descripción de los mecanismos y aludir a los desafíos futuros propuestos para ambos casos. (AU)

Spinal cord stimulation (SCS) is a neurophysiological technique that has shown to be effective in modulating motor dysfunction associated with devastating diseases such as: Parkinson's disease (PD) and spinal cord injuries. Considering that both pathologies have limited treatment options, SCS could be considered as a potential useful technique. The mechanism by which stimulation operates differs in both cases, generating changes in local circuits in the case of spinal cord injuries and supraspinal changes in PD. This review aims to analyze the effects of EES on both diseases, focusing in the results observed in animal models and patients, give a brief description of the mechanisms behind and postulate the future challenges proposed for SCS in both pathologies.(AU)

Spinal cord stimulation for Parkinson's disease: a systematic review.

Axial symptoms are a late-developing phenomenon in the course of Parkinson's disease (PD) and represent a therapeutic challenge given their poor response to levodopa therapy and deep brain stimulation. Spinal cord stimulation (SCS) may be a new therapeutic approach for the alleviation of levodopa-resistant motor symptoms of PD. Our purpose was to systematically review the effectiveness of SCS for the treatment of motor symptoms of PD and to evaluate the technical and pathophysiological mechanisms that may influence the outcome efficacy of SCS. A comprehensive literature search was conducted using electronic databases for the period from January 1966 through April 2014. The methodology utilized in this work follows a review process derived from evidence-based systematic review and meta-analysis of randomized trials described in the PRISMA statement. Reports examining SCS for the treatment of PD are limited. Eight studies with a total of 24 patients were included in this review. The overall motor score of the Unified Parkinson's Disease Rating Scale in the on/off-stimulation condition remained unchanged in 6 patients and improved in 18 patients after SCS. SCS appears to yield positive results for PD symptoms, especially for impairments in gait function and postural stability. However, evidence is limited and long-term prospective studies will be required to identify the optimal candidates for SCS and the best parameters of stimulation and to fully characterize the effects of stimulation on motor and nonmotor symptoms of PD.

Spinal cord stimulation alleviates motor deficits in a primate model of Parkinson disease.

Although deep brain electrical stimulation can alleviate the motor symptoms of Parkinson disease (PD), just a small fraction of patients with PD can take advantage of this procedure due to its invasive nature. A significantly less invasive method--epidural spinal cord stimulation (SCS)--has been suggested as an alternative approach for symptomatic treatment of PD. However, the mechanisms underlying motor improvements through SCS are unknown. Here, we show that SCS reproducibly alleviates motor deficits in a primate model of PD. Simultaneous neuronal recordings from multiple structures of the cortico-basal ganglia-thalamic loop in parkinsonian monkeys revealed abnormal highly synchronized neuronal activity within each of these structures and excessive functional coupling among them. SCS disrupted this pathological circuit behavior in a manner that mimics the effects caused by pharmacological dopamine replacement therapy or deep brain stimulation. These results suggest that SCS should be considered as an additional treatment option for patients with PD.

Chronic spinal cord electrical stimulation protects against 6-hydroxydopamine lesions.

Although L-dopa continues to be the gold standard for treating motor symptoms of Parkinson's disease (PD), it presents long-term complications. Deep brain stimulation is effective, but only a small percentage of idiopathic PD patients are eligible. Based on results in animal models and a handful of patients, dorsal column stimulation (DCS) has been proposed as a potential therapy for PD. To date, the long-term effects of DCS in animal models have not been quantified. Here, we report that DCS applied twice a week in rats treated with bilateral 6-OHDA striatal infusions led to a significant improvement in symptoms. DCS-treated rats exhibited a higher density of dopaminergic innervation in the striatum and higher neuronal cell count in the substantia nigra pars compacta compared to a control group. These results suggest that DCS has a chronic therapeutical and neuroprotective effect, increasing its potential as a new clinical option for treating PD patients.

Chronic in vivo multi-circuit neurophysiological recordings in mice.

While genetically modified mice have become a widely accepted tool for modeling the influence of gene function on the manifestation of neurological and psychiatric endophenotypes, only modest headway has been made in characterizing the functional circuit changes that underlie the disruption of complex behavioral processes in various models. This challenge partially arises from the fact that even simple behaviors require the coordination of many neural circuits vastly distributed across multiple brain areas. As such, many independent neurophysiological alterations are likely to yield overlapping circuit disruptions and ultimately lead to the manifestation of similar behavioral deficits. Here we describe the expansion of our neurophysiological recording approach in an effort to quantify neurophysiological activity across many large scale brain circuits simultaneously in freely behaving genetically modified mice. Using this expanded approach we were able to isolate up to 70 single neurons and record local field potential (LFP) activity simultaneously across 11 brain areas. Moreover, we found that these neurophysiological signals remained viable up to 16 months after implantation. Thus, our approach provides a powerful tool that will aid in dissecting the central brain network changes that underlie the complex behavioral deficits displayed by various genetically modified mice.

Restoration of locomotive function in Parkinson's disease by spinal cord stimulation: mechanistic approach.

Specific motor symptoms of Parkinson's disease (PD) can be treated effectively with direct electrical stimulation of deep nuclei in the brain. However, this is an invasive procedure, and the fraction of eligible patients is rather low according to currently used criteria. Spinal cord stimulation (SCS), a minimally invasive method, has more recently been proposed as a therapeutic approach to alleviate PD akinesia, in light of its proven ability to rescue locomotion in rodent models of PD. The mechanisms accounting for this effect are unknown but, from accumulated experience with the use of SCS in the management of chronic pain, it is known that the pathways most probably activated by SCS are the superficial fibers of the dorsal columns. We suggest that the prokinetic effect of SCS results from direct activation of ascending pathways reaching thalamic nuclei and the cerebral cortex. The afferent stimulation may, in addition, activate brainstem nuclei, contributing to the initiation of locomotion. On the basis of the striking change in the corticostriatal oscillatory mode of neuronal activity induced by SCS, we propose that, through activation of lemniscal and brainstem pathways, the locomotive increase is achieved by disruption of antikinetic low-frequency (<30 Hz) oscillatory synchronization in the corticobasal ganglia circuits.

Spinal cord stimulation restores locomotion in animal models of Parkinson's disease.

Dopamine replacement therapy is useful for treating motor symptoms in the early phase of Parkinson's disease, but it is less effective in the long term. Electrical deep-brain stimulation is a valuable complement to pharmacological treatment but involves a highly invasive surgical procedure. We found that epidural electrical stimulation of the dorsal columns in the spinal cord restores locomotion in both acute pharmacologically induced dopamine-depleted mice and in chronic 6-hydroxydopamine-lesioned rats. The functional recovery was paralleled by a disruption of aberrant low-frequency synchronous corticostriatal oscillations, leading to the emergence of neuronal activity patterns that resemble the state normally preceding spontaneous initiation of locomotion. We propose that dorsal column stimulation might become an efficient and less invasive alternative for treatment of Parkinson's disease in the future.

Neuronal activity of mitral-tufted cells in awake rats during passive and active odorant stimulation.

Odorants induce specific modulation of mitral/tufted (MT) cells' firing rate in the mammalian olfactory bulb (OB), inducing temporal patterns of neuronal discharge embedded in an oscillatory local field potential (LFP). While most studies have examined anesthetized animals, little is known about the firing rate and temporal patterns of OB single units and population activity in awake behaving mammals. We examined the firing rate and oscillatory activity of MT cells and LFP signals in behaving rats during two olfactory tasks: passive exposure (PE) and two-alternative (TA) choice discrimination. MT inhibitory responses are predominant in the TA task (76.5%), whereas MT excitatory responses predominate in the PE task (59.2%). Rhythmic discharge in the 12- to 100-Hz range was found in 79.0 and 68.9% of MT cells during PE and TA tasks, respectively. Most odorants presented in PE task increase rhythmic discharges at frequencies >50 Hz, whereas in TA, one of four odorants produced a modest increment <40 Hz. LFP oscillations were clearly modulated by odorants during the TA task, increasing their oscillatory power at frequencies centered at 20 Hz and decreasing power at frequencies >50 Hz. Our results indicate that firing rate responses of MT cells in awake animals are behaviorally modulated with inhibition being a prominent feature of this modulation. The occurrence of oscillatory patterns in single- and multiunitary discharge is also related to stimulation and behavioral context, while the oscillatory patterns of the neuronal population showed a strong dependence on odorant stimulation.

The infralimbic cortical area commands the behavioral and vegetative arousal during appetitive behavior in the rat.

The infralimbic cortical area is a good candidate to send processed motivational signals to initiate the arousing and autonomic responses that characterize appetitive behaviors. To test this hypothesis we enticed hungry rats with food while assessing locomotion (as an index of arousal level) and temperature responses, and evaluated Fos immunoreactivity (IR) in the infralimbic area and in subcortical nuclei involved in thermoregulation or arousal. We also recorded from single infralimbic neurons in freely moving rats while enticing them with food. We found that 83% of infralimbic neurons were excited or inhibited by feeding and, in particular, that 33% of infralimbic neurons increased their discharge rate during food enticing. Intact rats showed increased Fos IR in the infralimbic area, as well as in many other cortical areas. The excitotoxic lesion of the infralimbic cortex abolished the arousing and hyperthermic responses observed in intact rats, as well as the expression of Fos IR in the ascending arousal system and subcortical thermoregulatory regions. We conclude that the infralimbic area plays a central role in implementing behavioral arousing and thermal responses during an appetitive behavior.

Repressor element-1 silencing transcription/neuron-restrictive silencer factor is required for neural sodium channel expression during development of Xenopus.

The ability of neurons to fire rapid action potential relies on the expression of voltage-gated sodium channels; the onset of the transcription of genes that encode these channels occurs during early neuronal development. The factors that direct and regulate the specific expression of ion channels are not well understood. Repressor element-1 silencing transcription/neuron-restrictive silencer factor (REST/NRSF) is a transcriptional regulator characterized as a repressor of the expression of NaV1.2, the gene encoding the voltage-gated sodium channel most abundantly expressed in the CNS, as well as of the expression of numerous other neuronal genes. In mammals, REST/NRSF is expressed mostly in non-neural cell types and immature neurons, and it is downregulated on neural maturation. To understand the mechanisms that govern sodium channel gene transcription and to explore the role of REST/NRSF in vivo, we inhibited REST/NRSF action in developing Xenopus laevis embryos by means of a dominant negative protein or antisense oligonucleotides. Contrary to what was expected, these maneuvers result in the decrease of the expression of the NaV1.2 gene, as well as of other neuronal genes in the primary spinal neurons and cranial ganglia, without overt perturbation of neurogenesis. These results, together with the demonstration of robust REST/NRSF expression in primary spinal neurons, suggest that REST/NRSF is required for the acquisition of the differentiated functional neuronal phenotype during early development. Furthermore, they suggest that REST/NRSF may be used to activate or repress transcription of neuronal genes in distinct cellular and developmental contexts.