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Severe spinal cord injuries result in permanent paraparesis in spite of the frequent sparing of small portions of white matter. Spared fibre tracts are often incapable of maintaining and modulating the activity of lower spinal motor centres. Effects of rehabilitative training thus remain limited. Here, we activated spared descending brainstem fibres by electrical deep brain stimulation of the cuneiform nucleus of the mesencephalic locomotor region, the main control centre for locomotion in the brainstem, in adult female Lewis rats. We show that deep brain stimulation of the cuneiform nucleus enhances the weak remaining motor drive in highly paraparetic rats with severe, incomplete spinal cord injuries and enables high-intensity locomotor training. Stimulation of the cuneiform nucleus during rehabilitative aquatraining after subchronic (n = 8 stimulated versus n = 7 unstimulated versus n = 7 untrained rats) and chronic (n = 14 stimulated versus n = 9 unstimulated versus n = 9 untrained rats) spinal cord injury re-established substantial locomotion and improved long-term recovery of motor function. We additionally identified a safety window of stimulation parameters ensuring context-specific locomotor control in intact rats (n = 18) and illustrate the importance of timing of treatment initiation after spinal cord injury (n = 14). This study highlights stimulation of the cuneiform nucleus as a highly promising therapeutic strategy to enhance motor recovery after subchronic and chronic incomplete spinal cord injury with direct clinical applicability., Brain: A Journal of Neurology, 145 (10), ISSN:0006-8950, ISSN:1460-2156

Glutamatergic reticulospinal neurons in the gigantocellular reticular nucleus (GRN) of the medullary reticular formation can function as command neurons, transmitting motor commands to spinal cord circuits to instruct movement. Recent advances in our understanding of this neuron-dense region have been facilitated by the discovery of expression of the transcriptional regulator, Chx10, in excitatory reticulospinal neurons. Here, we address the capacity of local circuitry in the GRN to contribute to reticulospinal output. We define two subpopulations of Chx10-expressing neurons in this region, based on distinct electrophysiological properties and soma size (small and large), and show that these populations correspond to local interneurons and reticulospinal neurons, respectively. Using focal release of caged glutamate combined with patch clamp recordings, we demonstrated that Chx10 neurons form microcircuits in which the Chx10 local interneurons project to and facilitate the firing of Chx10 reticulospinal neurons. We discuss the implications of these microcircuits in terms of movement selection.

Background: The cuneiform nucleus is located in the center of the circuit that mediates autonomic responses to stress. Hemorrhagic hypotension leads to chemoreceptor anoxia, which consequently results in the reduction of baroreceptor discharge and stimulation of the chemoreceptor. Objective: Using the single-unit recording technique, the neuronal activities of the cuneiform nucleus were investigated in hypotensive states induced by hemorrhage and administration of an anti-hypertensive drug (hydralazine). Methods: Thirty male rats were divided into the control, hemorrhage, and hydralazine groups. The femoral artery was cannulated for the recording of cardiovascular responses, including systolic blood pressure, mean arterial pressure, and heart rate. Hydralazine was administered via tail vein. The single-unit recording was performed from the cuneiform nucleus. Results: The maximal systolic blood pressure and the mean arterial pressure significantly decreased and heart rate significantly increased after the application of hydralazine as well as the following hemorrhage compared to the control group. Hypotension significantly increased the firing rate of the cuneiform nucleus in both the hemorrhage and hydralazine groups compared to the control group. Conclusions: The present data indicate that the cuneiform nucleus activities following hypotension may play a crucial role in blood vessels and vasomotor tone. RESUMO Antecedentes: O núcleo cuneiforme está localizado no centro do circuito que media as respostas autonômicas ao estresse. A hipotensão hemorrágica leva à anóxia dos quimiorreceptores, que, consequentemente, resulta na redução da descarga dos barorreceptores e estimulação do quimiorreceptor. Objetivo: Utilizando a técnica de registro em unidade única, as atividades neuronais do núcleo cuneiforme foram investigadas em estados de hipotensão induzida por hemorragia e administração de um anti-hipertensivo (hidralazina). Métodos: Trinta ratos machos foram divididos nos grupos controle, hemorragia e hidralazina. A artéria femoral foi canulada, para o registro de respostas cardiovasculares, incluindo pressão arterial sistólica, pressão arterial média e frequência cardíaca. A hidralazina foi administrada na veia da cauda. O registro de unidade única foi realizado a partir do núcleo cuneiforme. Resultados: A pressão arterial sistólica máxima e a pressão arterial média diminuíram significativamente, e a frequência cardíaca aumentou significativamente após a aplicação de hidralazina, bem como a hemorragia seguinte, em comparação com o grupo controle. A hipotensão aumentou significativamente a taxa de disparo da população do núcleo cuneiforme em ambos os grupos de hemorragia e hidralazina, em comparação com o grupo de controle. Conclusões: Os presentes dados indicam que as atividades do núcleo cuneiforme após hipotensão podem desempenhar um papel crucial nos vasos sanguíneos e no tônus vasomotor.

Introduction: The mesencephalic reticular formation, isthmic reticular formation, microcellular tegmental nucleus, ventral tegmental area-parabrachial pigmented nucleus complex, and caudal-rostral linear nucleus of the raphe are small brainstem regions crucially involved in arousal, sleep, and reward. Yet, these nuclei are difficult to identify with magnetic resonance imaging (MRI) of living humans. In the current work, we developed a probabilistic atlas of these brainstem nuclei in living humans, using noninvasive ultra-high-field MRI. Methods: We acquired single-subject, multicontrast (diffusion and T(2)-weighted), 1.1-mm isotropic resolution, 7 Tesla MRI images of 12 healthy subjects. After preprocessing and alignment to the stereotactic space, these images were used to delineate (in each subject) the nuclei of interest based on the image contrast as well as on neighboring nuclei and landmarks. Nucleus labels were averaged across subjects to yield probabilistic labels. The latter were further validated by assessment of the label inter-rater agreement, internal consistency, and volume. Results: Labels were delineated for each nucleus with good overlap across subjects. The inter-rater agreement and internal consistency were below (p

Historically, the central mesencephalic reticular formation has been regarded as a purely horizontal gaze center based on the fact that electrical stimulation of this region produces horizontal saccades, it provides monosynaptic input to medial rectus motoneurons, and cells recorded in this region often display a peak in firing when horizontal saccades are made. We tested the proposition that the central mesencephalic reticular formation is purely a horizontal gaze center by examining whether this region also supplies terminals to superior rectus and levator palpebrae superioris motoneurons, both of which fire when making vertical eye movements. The experiments were carried out using dual tracer techniques at the light and electron microscopic level in macaque monkeys. Injections of biotinylated dextran amine or Phaseolus vulgaris leukoagglutinin into the central mesencephalic reticular formation produced anterogradely labeled terminals that were in synaptic contact with superior rectus and levator palpebrae superioris motoneurons that had been retrogradely labeled. These results indicate that this region is not purely connected with horizontal gaze motoneurons. In addition, we found that the number of contacts on vertical gaze motoneurons increased with more rostral injections involving the mesencephalic reticular formation adjacent to the interstitial nucleus of Cajal. This suggests that there is a caudal to rostral gradient for horizontal to vertical saccades, respectively, represented within the midbrain reticular formation. Finally, we utilized post-embedding immunohistochemistry to show that a portion of the labeled terminals were GABAergic, indicating they likely originate from downgaze premotor neurons.

In Parkinson's disease (PD), the loss of midbrain dopaminergic cells results in severe locomotor deficits, such as gait freezing and akinesia. Growing evidence indicates that these deficits can be attributed to the decreased activity in the mesencephalic locomotor region (MLR), a brainstem region controlling locomotion. Clinicians are exploring the deep brain stimulation of the MLR as a treatment option to improve locomotor function. The results are variable, from modest to promising. However, within the MLR, clinicians have targeted the pedunculopontine nucleus exclusively, while leaving the cuneiform nucleus unexplored. To our knowledge, the effects of cuneiform nucleus stimulation have never been determined in parkinsonian conditions in any animal model. Here, we addressed this issue in a mouse model of PD, based on the bilateral striatal injection of 6-hydroxydopamine, which damaged the nigrostriatal pathway and decreased locomotor activity. We show that selective optogenetic stimulation of glutamatergic neurons in the cuneiform nucleus in mice expressing channelrhodopsin in a Cre-dependent manner in Vglut2-positive neurons (Vglut2-ChR2-EYFP mice) increased the number of locomotor initiations, increased the time spent in locomotion, and controlled locomotor speed. Using deep learning-based movement analysis, we found that the limb kinematics of optogenetic-evoked locomotion in pathological conditions were largely similar to those recorded in intact animals. Our work identifies the glutamatergic neurons of the cuneiform nucleus as a potentially clinically relevant target to improve locomotor activity in parkinsonian conditions. Our study should open avenues to develop the targeted stimulation of these neurons using deep brain stimulation, pharmacotherapy, or optogenetics.

Discovery of the ascending reticular activating system (ARAS) can be attributed to work done in research neuroscientist Horace Magoun's laboratory. Before this finding, most scientists would focus on the diencephalon (and anterior midbrain) but not more caudally. Stimulation of the medial bulbar reticular formation in the pontine and midbrain tegmentum resulted disappearance of synchronized discharge and low-voltage fast activity. The effects were mediated by a thalamic projection system. This finding was a dramatic departure from the early philosophers' ascription of the awake soul to the ventricles (Galen), lumbosacral cord (Plato), pineal gland (Descartes), and even from more modern nineteenth- and twentieth-century hypotheses that the corpus striatum or periaqueductal gray matter housed the "seat of awareness." Magoun and his collaborators closed in on its true location in the cephalic brainstem-clinicians and neuropathologists would soon follow.

Basal ganglia play a central role in regulating behavior, but the organization of their outputs to other brain areas is incompletely understood. We investigate the largest output nucleus, the substantia nigra pars reticulata (SNr), and delineate the organization and physiology of its projection populations in mice. Using genetically targeted viral tracing and whole-brain anatomical analysis, we identify over 40 SNr targets that encompass a roughly 50-fold range of axonal densities. Retrograde tracing from the volumetrically largest targets indicates that the SNr contains segregated subpopulations that differentially project to functionally distinct brain stem regions. These subpopulations are electrophysiologically specialized and topographically organized and collateralize to common diencephalon targets, including the motor and intralaminar thalamus as well as the pedunculopontine nucleus and the midbrain reticular formation. These findings establish that SNr signaling is organized as dense, parallel outputs to specific brain stem targets concurrent with extensive collateral branches that encompass the majority of SNr axonal boutons.

International audience; Background and Purpose: Activation of the defence reaction inhibits the baroreflex response via the intermediate rostro-ventromedial medulla (B3 raphé) and nucleus tractus solitarius (NTS). Our aim was to determine whether and how baroreflex inhibition, induced by the disinhibition of the rostral cuneiform nucleus (part of the defence pathway), involves 5-HT neurons in B3 and 5-HT 3 receptors in the NTS. Experimental Approach: We performed immunohistochemistry and anatomical experiments to determine whether raphé 5-HT cells expressing Fos were directly targeted by the rostral cuneiform nucleus. The effect of blocking raphé 5-HT neurotransmission and NTS 5-HT 3 receptors on cuneiform-induced inhibition of the baroreflex cardiac response were also analysed. Key Results: Bicuculline, microinjected into the rostral cuneiform nucleus, induced an increase of double-labelled Fos-5-HT-IR cells in both the lateral paragigantocellular nucleus (LPGi) and raphé magnus. The anterograde tracer Phaseolus vulgaris leucoaggutinin injected into the rostral cuneiform nucleus revealed a dense projection to the LPGi but not raphé magnus. Cuneiform-induced baroreflex inhibition was prevented by B3 injection of 8-OH-DPAT, a selective 5-HT 1A receptor agonist. Cuneiform disinhibition also failed to inhibit the baroreflex bradycardia after NTS microinjection of the 5-HT 3 receptor antagonist granisetron and in 5-HT 3 receptor knockout mice. Conclusion and Implications: The rostral cuneiform nucleus participates in the defence inhibition of the baroreflex bradycardia via direct activation of the LPGi and via a projection to the raphé magnus to activate NTS 5-HT 3 receptors and inhibit second-order baroreflex neurons. These data bring new insights in primary and secondary mechanisms involved in vital baroreflex prevention during stress.

During normal viewing, we direct our eyes between objects in three-dimensional (3D) space many times a minute. To accurately fixate these objects, which are usually located in different directions and at different distances, we must generate eye movements with appropriate versional and vergence components. These combined saccade-vergence eye movements result in disjunctive saccades with a vergence component that is much faster than that generated during smooth, symmetric vergence eye movements. The neural control of disjunctive saccades is still poorly understood. Recent anatomical studies suggested that the central mesencephalic reticular formation (cMRF), located lateral to the oculomotor nucleus, contains premotor neurons potentially involved in the neural control of these eye movements. We have therefore investigated the role of the cMRF in the control of disjunctive saccades in trained rhesus monkeys. Here, we describe a unique population of cMRF neurons that, during disjunctive saccades, display a burst of spikes that are highly correlated with vergence velocity. Importantly, these neurons show no increase in activity for either conjugate saccades or symmetric vergence. These neurons are termed saccade-vergence burst neurons (SVBNs) to maintain consistency with modeling studies that proposed that such a class of neuron exists to generate the enhanced vergence velocities observed during disjunctive saccades. Our results demonstrate the existence and characteristics of SVBNs whose activity is correlated solely with the vergence component of disjunctive saccades and, based on modeling studies, are critically involved in the generation of the disjunctive saccades required to view objects in our 3D world.

Background We know little about the changes of brain activity in patients with normal-tension glaucoma (NTG). Purpose To investigate the altered spontaneous brain activity in patients with NTG through the resting state functional magnetic resonance imaging–fractional amplitude of low-frequency fluctuation (rsfMRI-fALFF) technique, and to explore the relationship with optical coherence tomography (OCT) and field of vision. Material and Methods Twenty patients with NTG and 20 healthy controls (HCs) (matched for sex, age, and level of education) were enrolled. Spontaneous cerebral activity variations were investigated using the rsfMRI-fALFF technique in all individuals. The average fALFF values of patients with NTG and HCs were compared. Results Compared with HCs, patients with NTG had significantly lower fALFF values in the right angular gyrus and precuneus; however, higher fALFF values in the brain regions were not observed. The values showed statistically significant negative correlation with those of the retinal nerve fiber layer (right angular gyrus: r = −0.607, P = 0.010; right precuneus: r = −0.504, P = 0.020). There was no significant correlation between the fALFF value and cup-disc ratio (right angular gyrus: r = 0.158, P = 0.494; right precuneus: r = −0.087, P = 0.706), mean deviation (right angular gyrus: r = 0.096, P = 0.468; right precuneus: r = 0.026, P = 0.845), and pattern SD value (right angular gyrus: r = 0.064, P = 0.626; right precuneus: r = −0.145, P = 0.268). Conclusion Abnormal spontaneous activities were detected in numerous brain regions of patients with NTG, which may provide useful information for understanding the dysfunction in NTG. These activity changes in brain regions may be used as effective clinical indicators for NTG.

Diagnoses of behavioral disorders such as autism spectrum disorder and schizophrenia are based on symptomatic descriptions that have been difficult to connect to mechanism. Although psychiatric genetics provide insight into the genetic underpinning of such disorders, with a majority of cases explained by polygenic factors, it remains difficult to design rational treatments. In this review, we highlight the value of understanding neural circuit function both as an intermediate-level of explanatory description that links gene to behavior as well as a pathway for developing rational diagnostics and therapeutics for behavioral disorders. As neural circuits perform hierarchically organized computational functions and give rise to network-level processes (e.g. macroscopic rhythms, goal-directed or homeostatic behaviors), correlated network-level deficits may indicate perturbation of a specific circuit. Therefore, identifying such correlated deficits or a ‘circuit endophenotype’ would provide a mechanistic point of entry, enhancing both diagnosis and treatment of a given behavioral disorder. We focus on a circuit endophenotype of the thalamic reticular nucleus (TRN) and how its impairment in neurodevelopmental disorders gives rise to a correlated set of readouts across sleep and attention. Because TRN neurons express several disorder-relevant genes identified through genome wide association studies, exploring the consequences of different TRN disruptions may be of broad translational significance.

SUMMARY The mesencephalic locomotor region (MLR) serves as an interface between higher-order motor systems and lower motor neurons. The excitatory module of the MLR is composed of the pedunculopontine nucleus (PPN) and the cuneiform nucleus (CnF), and their activation has been proposed to elicit different modalities of movement. However, how the differences in connectivity and physiological properties explain their contributions to motor activity is not well known. Here we report that CnF glutamatergic neurons are more electrophysiologically homogeneous than PPN neurons and have mostly short-range connectivity, whereas PPN glutamatergic neurons are heterogeneous and maintain long-range connections, most notably with the basal ganglia. Optogenetic activation of CnF neurons produces short-lasting muscle activation, driving involuntary motor activity. In contrast, PPN neuron activation produces long-lasting increases in muscle tone that reduce motor activity and disrupt gait. Our results highlight biophysical and functional attributes among MLR neurons that support their differential contribution to motor behavior., In brief Dautan et al. show key differences in the connectivity and physiological properties of neurons of the mesencephalic locomotor region. Although activation of CnF neurons elicits involuntary locomotor responses, activation of PPN neurons increases muscle tone and reduces motor activity, suggesting that PPN encodes a readiness signal that precedes locomotion., Graphical Abstract

Significance Learning is thought to be mediated by activity-dependent modification of neuronal interactions. To avoid maladaptive modifications of synaptic transmission by spurious activity, synaptic plasticity has to be gated. In the case of supervised learning, these gating functions are accomplished by reinforcement through value-assigning systems. Here we show that the dynamic state of local circuits correlates with the occurrence of activity-dependent long-term changes in neuronal response properties. We find that repeated visual stimuli induce long-term changes of orientation preference of neuronal populations in visual cortex if stimuli induce synchronized population responses oscillating at ɣ-frequencies. This suggests that neuronal plasticity is controlled by a hierarchy of gating systems and assigns critical gating functions to resonance properties of local circuits., Use-dependent long-term changes of neuronal response properties must be gated to prevent irrelevant activity from inducing inappropriate modifications. Here we test the hypothesis that local network dynamics contribute to such gating. As synaptic modifications depend on temporal contiguity between presynaptic and postsynaptic activity, we examined the effect of synchronized gamma (ɣ) oscillations on stimulation-dependent modifications of orientation selectivity in adult cat visual cortex. Changes of orientation maps were induced by pairing visual stimulation with electrical activation of the mesencephalic reticular formation. Changes in orientation selectivity were assessed with optical recording of intrinsic signals and multiunit recordings. When conditioning stimuli were associated with strong ɣ-oscillations, orientation domains matching the orientation of the conditioning grating stimulus became more responsive and expanded, because neurons with preferences differing by less than 30° from the orientation of the conditioning grating shifted their orientation preference toward the conditioned orientation. When conditioning stimuli induced no or only weak ɣ-oscillations, responsiveness of neurons driven by the conditioning stimulus decreased. These differential effects depended on the power of oscillations in the low ɣ-band (20 Hz to 48 Hz) and not on differences in discharge rate of cortical neurons, because there was no correlation between the discharge rates during conditioning and the occurrence of changes in orientation preference. Thus, occurrence and polarity of use-dependent long-term changes of cortical response properties appear to depend on the occurrence of ɣ-oscillations during induction and hence on the degree of temporal coherence of the change-inducing network activity.

The sudden infant death syndrome (SIDS) is the leading cause of postneonatal infant mortality in the United States today, with an overall rate of 0.39/1000 live births. It is defined as the sudden and unexpected death of an infant

The presence of opioid receptors in the cuneiform nucleus (CnF), which is a mesencephalic area, and their involvement in the central cardiovascular responses have been shown. Therefore, this study is designed to examine the possible role of mu- (μ) and delta- (δ) opioid receptors in the CnF in the cardiovascular responses in normotensive and hemorrhagic hypotensive rats. Following anesthesia and the recording of the blood pressure, the agonist and antagonist of μ- (morphine and naloxone) and δ- (D-Pen 2, 5]-Enkephalin hydrate (DPDPE) and naltridole) receptors were microinjected into the CnF. In the hemorrhagic groups, the drugs were microinjected into the nucleus 2 min after withdrawing 15 % of the total blood volume (TBV). Time-course changes (Δ) in the mean arterial pressure (MAP), systolic blood pressure (SBP), and heart rate (HR) were obtained and compared with the control and hemorrhage groups. Microinjecting morphine in both normotensive and hemorrhagic rats significantly decreased ΔSBP, ΔMAP, and ΔHR; also, naloxone significantly increased all these parameters. The cardiovascular effects of DPDPE and naltridole were not significant in the normotensive rats; however, DPDPE attenuated only the tachycardia induced by the hypotensive hemorrhage. The findings of this study revealed that the opioid receptors in the CnF had an inhibitory effect on the cardiovascular parameters in both normotensive and hypotensive hemorrhagic conditions and these effects were mostly mediated by μ-opioid receptors.

We attempted to investigate postural instability in patients with injury of the corticoreticular pathway (CRP) after mild traumatic brain injury.The CRP was reconstructed, and the fractional anisotropy value, apparent diffusion coefficient value, and fiber volume of the CRP were measured. For evaluation of postural instability, both the Balance Error Scoring System score and the displacement of center of pressure were measured.Significantly lower tract volume of the CRP was observed in the patient group than in the control group with no significant difference in fractional anisotropy and apparent diffusion coefficient values(P0.05). The results of the Balance Error Scoring System shown on a firm and foam surface were significantly higher in the patient group than in the control group (P0.05). Significant increments in displacement of center of pressure for 3 stances of double-leg, single-leg, and tandem stances in distance, maximum distance, and path length were observed in the patient group compared with the control group (P0.05). By contrast, no significant difference in the double stance on the x axis of the distance was observed between the patient and control groups (P0.05).We demonstrated postural instability in patients with injury of the CRP following mild traumatic brain injury.

Stroke is an example of neurological diseases that can commonly drives Excessive Daytime Sleepiness (EDS). Extensive strokes with brain edema can leave a brain herniation and coma. Other causes of EDS after stroke are strategic lesions at Thalamus and brainstein. A 56-year-old man, right handed, with hypertension and hypercholesterolemia was admitted at Emergency Room due to 5 days onset of EDS, memory impairment, and left-sided weakness. A brain magnetic resonance imaging showed paramedian thalamic hyperintensity with rostral midbrain hyperintensity extending along the pial surface of the interpeduncular fossa. The artery of Percheron (AP) is an unusual anatomical variation that originates from the posterior cerebral artery and irrigates the paramedian regions of the thalamus and part of the midbrain. It is important the clinical suspicions with detailed drowsy patients history. Awareness of the clinical and neuroimaging features of this stroke syndrome is essential for timely diagnosis and appropriate management.

Neurons in the medullary reticular formation are involved in the control of postural and locomotor behaviors in all vertebrates. Reticulospinal neurons in this brain region provide one of the major descending projections to the spinal cord. Although neurons in the newt medullary reticular formation have been extensively studied using in vivo extracellular recordings, little is known of their intrinsic biophysical properties or of the underlying circuitry of this region. Using whole cell patch-clamp recordings in brain slices containing the rostromedial reticular formation from adult male newts, we observed spontaneous miniature outward currents (SMOCs) in ~2/3 of neurons. Although SMOCs superficially resembled inhibitory postsynaptic currents (IPSCs), they had slower risetimes and decay times than spontaneous IPSCs. SMOCs required intracellular Ca2+release from ryanodine receptors and were also dependent on the influx of extracellular Ca2+. SMOCs were unaffected by apamin but were partially blocked by iberiotoxin and charybdotoxin, indicating that SMOCs were mediated by big-conductance Ca2+-activated K+channels. Application of the sarco/endoplasmic Ca2+ATPase inhibitor cyclopiazonic acid blocked the generation of SMOCs and also increased neural excitability. Neurons with SMOCs had significantly broader action potentials, slower membrane time constants, and higher input resistance than neurons without SMOCs. Thus, SMOCs may serve as a mechanism to regulate action potential threshold in a majority of neurons within the newt medullary reticular formation.NEW & NOTEWORTHY The medullary reticular formation exerts a powerful influence on sensorimotor integration and subsequent motor behavior, yet little is known about the neurons involved. In this study, we identify a transient potassium current that regulates action potential threshold in a majority of medullary reticular neurons.

The mesencephalic locomotor region (MLR) is an important integrative area for the initiation and modulation of locomotion. Recently it has been realized that dopamine (DA) projections from the substantia nigra pars compacta project to the MLR. Here we explore DA projections from an area of the medial zona incerta (ZI) known for its role in motor control onto the MLR. We provide evidence that dopaminergic (DAergic) A13 neurons have connectivity to the cuneiform nucleus (CnF) and pedunculopontine tegmental nucleus (PPTg) of the MLR. No ascending connectivity to the dorsolateral striatum was observed. On the other hand, DAergic A13 projections to the medullary reticular formation (MRF) and the lumbar spinal cord were sparse. A small number of non-DAergic neurons within the medial ZI projected to the lumbar spinal cord. We then characterized the DA A13 cells and report that these cells differ from canonical DA neurons since they lack the Dopamine Transporter (DAT). The lack of DAT expression, and possibly the lack of a dopamine reuptake mechanism, points to a longer time of action compared to typical dopamine neurons. Collectively our data suggest a parallel descending DAergic pathway from the A13 neurons of the medial ZI to the MLR, which we expect is important for modulating movement.

Aims Topiramate causes the inhibition of alcohol consumption in addicts but the mechanism of this action has not been fully understood yet. Nowadays, it seems that memory may have a role in the development of dependence. In this study, the impact of topiramate and ethanol on the bioelectric activity of the brain in rabbits and on spatial memory in rats was evaluated. Short summary The aim of the study was to assess the effect of co-administration of topiramate and ethanol on bioelectric activity of the rabbits' brain and on spatial memory in rats. Topiramate decreased ethanol-induced changes in all studied brain structures and improved memory and learning processes. Methods A pharmaco-electroencephalography study was used to examine the effect of topiramate (25 mg/kg/day) co-administered for 6 weeks with ethanol on the bioelectric activity of the rabbits' brain. The influence of the drug was also assessed in first and second weeks of the abstinence period. Spatial memory was evaluated in rats using Morris water maze task. Topiramate (60 mg/kg/day) was administered with the ethanol for 3 weeks and for 2 weeks in the abstinence. Results After 6 weeks of topiramate and ethanol administration, the drug decreased ethanol-induced changes in the midbrain reticular formation, hippocampus and frontal cortex. In the abstinence, the drug also inhibited the features of neuronal hyperactivity, especially in the hippocampus. Moreover, topiramate co-administered with ethanol for 3 weeks decreased ethanol-induced memory disturbance in rats. This beneficial effect was also observed in the second week of abstinence. Conclusion These findings reveal that 'antialcoholic' activity of topiramate may be associated with its advantageous effect on memory and learning processes.

Conventional deep brain stimulation (DBS) applies constant electrical stimulation to specific brain regions to treat neurological disorders. Closed-loop DBS with real-time feedback is gaining attention in recent years, after proved more effective than conventional DBS in terms of pathological symptom control clinically. Here we demonstrate the conceptualization and validation of a closed-loop DBS system using open-source hardware. We used hippocampal theta oscillations as system input, and electrical stimulation in the mesencephalic reticular formation (mRt) as controller output. It is well documented that hippocampal theta oscillations are highly related to locomotion, while electrical stimulation in the mRt induces freezing. We used an Arduino open-source microcontroller between input and output sources. This allowed us to use hippocampal local field potentials (LFPs) to steer electrical stimulation in the mRt. Our results showed that closed-loop DBS significantly suppressed locomotion compared to no stimulation, and required on average only 56% of the stimulation used in open-loop DBS to reach similar effects. The main advantages of open-source hardware include wide selection and availability, high customizability, and affordability. Our open-source closed-loop DBS system is effective, and warrants further research using open-source hardware for closed-loop neuromodulation.

Astrocytic Ca2+-mediated gliovascular interactions regulate the neurovascular network in situ and in vivo. However, it is difficult to measure directly both the astrocytic activity and fMRI to relate the various forms of blood-oxygen-level-dependent (BOLD) signaling to brain states under normal and pathological conditions. In this study, fMRI and GCaMP-mediated Ca2+ optical fiber recordings revealed distinct evoked astrocytic Ca2+ signals that were coupled with positive BOLD signals and intrinsic astrocytic Ca2+ signals that were coupled with negative BOLD signals. Both evoked and intrinsic astrocytic calcium signal could occur concurrently or respectively during stimulation. The intrinsic astrocytic calcium signal can be detected globally in multiple cortical sites in contrast to the evoked astrocytic calcium signal only detected at the activated cortical region. Unlike propagating Ca2+ waves in spreading depolarization/depression, the intrinsic Ca2+ spikes occurred simultaneously in both hemispheres and were initiated upon the activation of the central thalamus and midbrain reticular formation. The occurrence of the intrinsic astrocytic calcium signal is strongly coincident with an increased EEG power level of the brain resting-state fluctuation. These results demonstrate highly correlated astrocytic Ca2+ spikes with bidirectional fMRI signals based on the thalamic regulation of cortical states, depicting a brain-state dependency of both astrocytic Ca2+ and BOLD fMRI signals.

New antiepileptic drugs have been investigated for their potential role in the treatment of alcohol dependence. One of these drugs is retigabine and this study examines the effect of retigabine co-administered with ethanol on the development of alcohol dependence and the course of acute withdrawal syndrome. A pharmaco-EEG method was used to examine this impact in selected brain structures of rabbits (midbrain reticular formation, hippocampus and frontal cortex). Retigabine was administered p.o. at a dose of 5mg/kg/day with ethanol ad libitum for 6 weeks and then alone for 2 weeks during an abstinence period. Changes in bioelectric activity, which demonstrated the inhibitory effect of alcohol on the brain structures, were already visible after 2 weeks of ethanol administration. In the abstinence period, changes were of a different nature and significant neuronal hyperactivity was observed, particularly in the midbrain reticular formation and the hippocampus. This findings reveal that retigabine decreased ethanol-induced changes during both alcohol administration and abstinence periods. In particular, the modulatory effect of retigabine on the hippocampus may be a significant element of its mechanism of action in alcohol dependence therapy.

Substantial evidence has suggested that deep brain stimulation of the cuneiform nucleus has become a remarkable treatment option for intractable pain, but the possible mechanism is poorly understood. Using a melanocortin-4 receptor (MC4R)-green fluorescent protein (GFP) reporter knockin mouse, we showed that a large number of MC4R-GFP-positive neurons were expressed in the cuneiform nucleus. Immunofluorescence revealed that approximately 40%-50% of MC4R-GFP-positive neurons expressed mu opioid receptors, indicating that they were opioidergic signaling. Our findings support the hypothesis that MC4R expression in the cuneiform nucleus is involved in the modulation of opioidergic signaling.

Repetitive electrical microstimulation to the cortical masticatory area (CMA) evokes distinct patterns of rhythmical jaw muscle activities (RJMAs) in animals. This study aimed to investigate the characteristics of the descending projections from the CMA, associated with distinct patterns of RJMAs, to the thalamus, midbrain, pons and medulla in guinea pigs. RJMAs with continuous masseter and digastric bursts (CB-RJMAs) and stimulus-locked digastric sub-bursts (SLB-RJMAs) were induced from the anterior and posterior areas of the rostral region of the lateral agranular cortex, and chewing-like RJMAs from the rostral region of the granular cortex. Anterograde tracer, biotinylated dextran amine, was injected into the three cortical areas. The cortical area inducing CB-RJMAs had strong ipsilateral projections to the motor thalamus, red nucleus, midbrain reticular formation, superior colliculus, parabrachial nucleus, and supratrigeminal region, and contralateral projections mainly to the lateral reticular formation around the trigeminal motor nucleus (Vmo). The cortical area inducing SLB-RJMAs had moderate projections to the motor thalamus and lateral reticular formation around the Vmo, but few projections to the midbrain nuclei. The cortical area inducing chewing-like RJMAs had strong projections to the ipsilateral sensory thalamus and contralateral trigeminal sensory nuclei, and moderate projections to the lateral reticular formation. The three cortical areas consistently had few projections to the ventromedial reticular formation. The present study demonstrates that multiple direct and indirect descending projections from the CMA onto the premotor systems connecting the trigeminal motoneurons represent the neuroanatomical repertoires for generating RJMAs during the distinct phases of natural ingestive behavior.

The central mesencephalic reticular formation is physiologically implicated in oculomotor function and anatomically interwoven with many parts of the oculomotor system’s premotor circuitry. This study in Macaca fascicularis monkeys investigates the pattern of central mesencephalic reticular formation projections to the area in and around the extraocular motor nuclei, with special emphasis on the supraoculomotor area. It also examines the location of the cells responsible for this projection. Injections of biotinylated dextran amine were stereotaxically placed within the central mesencephalic reticular formation to anterogradely label axons and terminals. These revealed bilateral terminal fields in the supraoculomotor area. In addition, dense terminations were found in both the preganglionic Edinger-Westphal nuclei. The dense terminations just dorsal to the oculomotor nucleus overlap with the location of the C-group medial rectus motoneurons projecting to multiply innervated muscle fibers suggesting they may be targeted. Minor terminal fields were observed bilaterally within the borders of the oculomotor and abducens nuclei. Injections including the supraoculomotor area and oculomotor nucleus retrogradely labeled a tight band of neurons crossing the central third of the central mesencephalic reticular formation at all rostrocaudal levels, indicating a subregion of the nucleus provides this projection. Thus, these experiments reveal that a subregion of the central mesencephalic reticular formation may directly project to motoneurons in the oculomotor and abducens nuclei, as well as to preganglionic neurons controlling the tone of intraocular muscles. This pattern of projections suggests an as yet undetermined role in regulating the near triad.

We attempted to investigate the anatomical location of the corticoreticular pathway (CRP) in the subcortical white matter in the human. Thirty-three healthy volunteers were recruited. The locations of the CRP and corticospinal tract (CST) were defined as the location on axial slice of the centrum semiovale, corona radiata, and posterior limb of the internal capsule. The CRP was located close antero-medially to the CST in all three regions of subcortical white matter.