Layer 5 Intratelencephalic Neurons in the Motor Cortex Stably Encode Skilled Movement.

The primary motor cortex (M1) and the dorsal striatum play a critical role in motor learning and the retention of learned behaviors. Motor representations of corticostriatal ensembles emerge during motor learning. In the coordinated reorganization of M1 and the dorsal striatum for motor learning, layer 5a (L5a) which connects M1 to the ipsilateral and contralateral dorsal striatum, should be a key layer. Although M1 L5a neurons represent movement-related activity in the late stage of learning, it is unclear whether the activity is retained as a memory engram. Here, using Tlx3-Cre male transgenic mice, we conducted two-photon calcium imaging of striatum-projecting L5a intratelencephalic (IT) neurons in forelimb M1 during late sessions of a self-initiated lever-pull task and in sessions after 6 d of nontraining following the late sessions. We found that trained male animals exhibited stable motor performance before and after the nontraining days. At the same time, we found that M1 L5a IT neurons strongly represented the well-learned forelimb movement but not uninstructed orofacial movements. A subset of M1 L5a IT neurons consistently coded the well-learned forelimb movement before and after the nontraining days. Inactivation of M1 IT neurons after learning impaired task performance when the lever was made heavier or when the target range of the pull distance was narrowed. These results suggest that a subset of M1 L5a IT neurons continuously represent skilled movement after learning and serve to fine-tune the kinematics of well-learned movement.SIGNIFICANCE STATEMENT Motor memory persists even when it is not used for a while. IT neurons in L5a of the M1 gradually come to represent skilled forelimb movements during motor learning. However, it remains to be determined whether these changes persist over a long period and how these neurons contribute to skilled movements. Here, we show that a subset of M1 L5a IT neurons retain information for skilled forelimb movements even after nontraining days. Furthermore, suppressing the activity of these neurons during skilled forelimb movements impaired behavioral stability and adaptability. Our results suggest the importance of M1 L5a IT neurons for tuning skilled forelimb movements over a long period.

[Anatomical observation and CT three-dimensional reconstruction of Five-shu acupoints of Shaoyin Heart Meridian in rabbit's forelimb].

OBJECTIVE: To investigate the location and anatomical structure of "Shaochong"(HT9), "Shaofu"(HT8), "Shenmen"(HT7), "Lingdao"(HT4) and "Shaohai"(HT3) in the rabbit's forelimb. METHODS: Sixteen rabbits (half male and half female) were used in the present study. By referring to the national standards on the location of acupoints in the human body and the literature about the location of acupoints in the rabbit, and by using the method of comparative anatomy, the location and needling operation of the Five-shu acupoints of Shaoyin Heart Meridian on the rabbit's forelimb were defined, and these acupoints were needled and CT three-dimensional reconstruction were conducted. Then, the rabbits were killed, and intravascular perfusion was performed, followed by inserting acupuncture needles into these five acupoints for observing the anatomical relationship between the inserted acupuncture needle and the structure of surrounding tissues. RESULTS: HT9 is located at the medial side of the little finger of forelimb, about 1 mm beside the nail root, and is adjacent to the superficial flexor tendon of the finger, the dorsal branches of the proper palmar digital artery and vein, and the endings of dorsal branch of palmar digital proper nerve of the ulnar nerve on the fifth finger side. HT8 is located at the palm side of the forelimb, horizontally parallel to the proximal end of the 5th metacarpophalangeal joint and between the 4th and 5th metacarpal bones, and is adjacent to the lumbricalis, the 4th and 5th interossei, and common palmar digital artery and vein and the palmar digital proper nerve of the ulnar nerve. HT7 is located at the medial margin of the extensor carpal tendon on the ulnar side, between the distal end of the ulna and the ulnar carpal bone, and is adjacent to the tendons of flexor carpi ulnaris and extensor carpi ulnaris, ulnar artery, ulnar vein and ulnar nerve. HT4 is located at the medial border of the ulnar flexor tendon, about 1.5 cun superior to HT7, and is adjacent to extensor carpi ulnaris, flexor carpi ulnaris, flexor digitorum superficialis, flexor digitorum profundus, ulnar artery, vein and ulnar nerve. HT3 is located at the depression, medial to the condyle of humerus when the elbow is bent at 90°, its neighbor structure is composed of pronator teres, biceps brachii, brachial artery and vein, radial collateral artery, radial collateral vein, medial antebrachial cutaneous nerve and median nerve. CONCLUSION: In the rabbit, there is a close relationship between HT9, HT8, HT7, HT4 and HT3 regions and brachial vascular and its branches, cephalic vein and its branches, medial antebrachial cutaneous nerve, median nerve and ulnar nerve, which is the morphological basis of the Five-shu acupoints of Shaoyin Heart Meridian for treating some related clinical disorders.

Pneumatic compression therapy using the EQ Press accelerates lymphatic flow in healthy equine forelimbs as determined by lymphoscintigraphy.

OBJECTIVE: Limb lymphedema in horses can be debilitating and painful. Pneumatic compression therapy has shown significant benefits for people suffering from lymphedema. The objective of this study was to determine the effect of a novel, equine-specific pneumatic compression device on the lymphatic flow of healthy horse forelimbs as determined by Tc-99m sulfur colloid lymphoscintigraphy. ANIMALS: 6 healthy Thoroughbreds. PROCEDURES: In a randomized crossover design, horses underwent bilateral forelimb lymphoscintigraphy following subcutaneous injection of Tc-99m sulfur colloid at the coronary band as untreated control or with pneumatic compression therapy using the EQ Press. Lateral, static images were obtained of the distal limb (time 0 to 60 minutes) and proximal limb (time 30 to 60 minutes) using a standard gamma camera. Lymphatic flow was determined by assigning a score to the time point at which Tc-99m sulfur colloid was first visualized at the level of the accessory carpal bone (1 to 7) in the distal limb and the cubital lymph node (1 to 4) in the proximal limb. RESULTS: EQ Press treatment led to a significantly faster lymphatic flow of Tc-99m sulfur colloid to the predetermined anatomic locations of the accessory carpal bone (P = .002) in the distal limb and the cubital lymph node (P = .001) in the proximal limb. CLINICAL RELEVANCE: Pneumatic compression therapy as provided by an equine-specific device encouraged lymphatic flow in healthy, nonedematous equine forelimbs. These data support further study of the EQ Press for pneumatic compression therapy in horses clinically affected by lymphedema and lymphatic drainage disorders.

The deep cerebellar nuclei to striatum disynaptic connection contributes to skilled forelimb movement.

Cerebellar-thalamo-striatal synaptic communication has been implicated in a wide range of behaviors, including goal-directed actions, and is altered in cerebellar dystonia. However, its detailed connectivity through the thalamus and its contribution to the execution of forelimb movements is unclear. Here, we use trans-synaptic and retrograde tracing, ex vivo slice recordings, and optogenetic inhibitions during the execution of unidirectional or sequential joystick displacements to demonstrate that the deep cerebellar nuclei (DCN) influence the dorsal striatum with a very high probability. We show that this mainly occurs through the centrolateral (CL), parafascicular (PF), and ventrolateral (VL) nuclei of the thalamus, observing that the DCN→VL and DCN→CL pathways contribute to the execution of unidirectional forelimb displacements while the DCN→PF and DCN→thalamo→striatal pathways contribute to the appropriate execution of forelimb reaching and sequential displacements. These findings highlight specific contributions of the different cerebellar-thalamo-striatal paths to the control of skilled forelimb movement.

Patterned Stimulation of the Chrimson Opsin in Glutamatergic Motor Thalamus Neurons Improves Forelimb Akinesia in Parkinsonian Rats.

Parkinson's disease (PD) is a motor disorder charactertised by altered neural activity throughout the basal ganglia-thalamocortical circuit. Electrical deep brain stimulation (DBS) is efficacious in alleviating motor symptoms, but has several notable side-effects, most likely reflecting the non-specific nature of electrical stimulation and/or the brain regions targeted. We determined whether specific optogenetic activation of glutamatergic motor thalamus (Mthal) neurons alleviated forelimb akinesia in a chronic rat model of PD. Parkinsonian rats (unilateral 6-hydroxydopamine injection) were injected with an adeno-associated viral vector (AAV5-CaMKII-Chrimson-GFP) to transduce glutamatergic Mthal neurons with the red-shifted Chrimson opsin. Optogenetic stimulation with orange light at 15 Hz tonic and a physiological pattern, previously recorded from a Mthal neuron in a control rat, significantly increased forelimb use in the reaching test (p < 0.01). Orange light theta burst stimulation, 15 Hz and control reaching patterns significantly reduced akinesia (p < 0.0001) assessed by the step test. In contrast, forelimb use in the cylinder test was unaffected by orange light stimulation with any pattern. Blue light (control) stimulation failed to alter behaviours. Activation of Chrimson using complex patterns in the Mthal may be an alternative treatment to recover movement in PD. These vector and opsin changes are important steps towards translating optogenetic stimulation to humans.

Large-scale all-optical dissection of motor cortex connectivity shows a segregated organization of mouse forelimb representations.

In rodent motor cortex, the rostral forelimb area (RFA) and the caudal forelimb area (CFA) are major actors in orchestrating the control of complex forelimb movements. However, their intrinsic connectivity and reciprocal functional organization are still unclear, limiting our understanding of how the brain coordinates and executes voluntary movements. Here, we causally probe cortical connectivity and activation patterns triggered by transcranial optogenetic stimulation of ethologically relevant complex movements exploiting a large-scale all-optical method in awake mice. Results show specific activation features for each movement class, providing evidence for a segregated functional organization of CFA and RFA. Importantly, we identify a second discrete lateral grasping representation area, namely the lateral forelimb area (LFA), with unique connectivity and activation patterns. Therefore, we propose the LFA as a distinct forelimb representation in the mouse somatotopic motor map.

Movement-specific signaling is differentially distributed across motor cortex layer 5 projection neuron classes.

Motor cortex generates descending output necessary for executing a wide range of limb movements. Although movement-related activity has been described throughout motor cortex, the spatiotemporal organization of movement-specific signaling in deep layers remains largely unknown. Here we record layer 5B population dynamics in the caudal forelimb area of motor cortex while mice perform a forelimb push/pull task and find that most neurons show movement-invariant responses, with a minority displaying movement specificity. Using cell-type-specific imaging, we identify that invariant responses dominate pyramidal tract (PT) neuron activity, with a small subpopulation representing movement type, whereas a larger proportion of intratelencephalic (IT) neurons display movement-type-specific signaling. The proportion of IT neurons decoding movement-type peaks prior to movement initiation, whereas for PT neurons, this occurs during movement execution. Our data suggest that layer 5B population dynamics largely reflect movement-invariant signaling, with information related to movement-type being routed through relatively small, distributed subpopulations of projection neurons.

Thalamic activations in rat brain by fMRI during tactile (forepaw, whisker) and non-tactile (visual, olfactory) sensory stimulations.

The thalamus is a crucial subcortical hub that impacts cortical activity. Tracing experiments in animals and post-mortem humans suggest rich morphological specificity of the thalamus. Very few studies reported rodent thalamic activations by functional MRI (fMRI) as compared to cortical activations for different sensory stimuli. Here, we show different portions of the rat thalamus in response to tactile (forepaw, whisker) and non-tactile (visual, olfactory) sensory stimuli with high field fMRI (11.7T) using a custom-build quadrature surface coil to capture high sensitivity signals from superficial and deep brain regions simultaneously. Results demonstrate reproducible thalamic activations during both tactile and non-tactile stimuli. Forepaw and whisker stimuli activated broader regions within the thalamus: ventral posterior lateral (VPL), ventral posterior medial (VPM), lateral posterior mediorostral (LPMR) and posterior medial (POm) thalamic nuclei. Visual stimuli activated dorsal lateral geniculate nucleus (DLG) of the thalamus but also parts of the superior/inferior colliculus, whereas olfactory stimuli activated specifically the mediodorsal nucleus of the thalamus (MDT). BOLD activations in LGN and MDT were much stronger than in VPL, VPM, LPMR and POm. These fMRI-based thalamic activations suggest that forepaw and whisker (i.e., tactile) stimuli engage VPL, VPM, LPMR and POm whereas visual and olfactory (i.e., non-tactile) stimuli, respectively, recruit DLG and MDT exclusively.

A positive association of larval therapy and hyperbaric oxygen therapy in veterinary wound care.

The treatment of cutaneous wounds is part of the veterinary routine from initial scientific reports due to being regularly present condition. Currently, several types of treatments are available to accelerate the healing process. This report presents the case of a dog with multiple lesions in the thoracic limbs resulting from a car accident, who underwent larval therapy and hyperbaric oxygen therapy (HBOT). The animal was a 2-year-old female mixed breed dog presenting severe skin degloving, fracture in the left thoracic limb (LTL), with abrasion lesions and dislocation in the right thoracic limb (RTL). The animal underwent multiple modality therapies, such as HBOT sessions associated with larval therapy; even after the LTL presented gangrene, this treatment resulted in optimal viability of the non-necrotic tissue adjacent to the gangrene. Due to chronic pain unresponsive to drug control and the presence of a fracture at a location where a possible exoprosthesis was supposed to be fixed, the LTL ended up being amputated. There are several reports of the use of HBOT or larval therapy in traumatized limbs; however, the combination of both therapies has not been previously described in the veterinary literature. Thus, we demonstrate through this report that it was possible to quickly recover the animal with good wound resolution through tissue oxygenation and a healthy granulation bed, both provided by the therapeutic combination.

Spatiotemporal structure of sensory-evoked and spontaneous activity revealed by mesoscale imaging in anesthetized and awake mice.

Stimuli-evoked and spontaneous brain activity propagates across the cortex in diverse spatiotemporal patterns. Despite extensive studies, the relationship between spontaneous and evoked activity is poorly understood. We investigate this relationship by comparing the amplitude, speed, direction, and complexity of propagation trajectories of spontaneous and evoked activity elicited with visual, auditory, and tactile stimuli using mesoscale wide-field imaging in mice. For both spontaneous and evoked activity, the speed and direction of propagation is modulated by the amplitude. However, spontaneous activity has a higher complexity of the propagation trajectories. For low stimulus strengths, evoked activity amplitude and speed is similar to that of spontaneous activity but becomes dissimilar at higher stimulus strengths. These findings are consistent with observations that primary sensory areas receive widespread inputs from other cortical regions, and during rest, the cortex tends to reactivate traces of complex multisensory experiences that might have occurred in exhibition of different behaviors.

Interhemispheric Cortico-Cortical Pathway for Sequential Bimanual Movements in Mice.

Animals precisely coordinate their left and right limbs for various adaptive purposes. While the left and right limbs are clearly controlled by different cortical hemispheres, the neural mechanisms that determine the action sequence between them remains elusive. Here, we have established a novel head-fixed bimanual-press (biPress) sequence task in which mice sequentially press left and right pedals with their forelimbs in a predetermined order. Using this motor task, we found that the motor cortical neurons responsible for the first press (1P) also generate independent motor signals for the second press (2P) by the opposite forelimb during the movement transitions between forelimbs. Projection-specific calcium imaging and optogenetic manipulation revealed these motor signals are transferred from one motor cortical hemisphere to the other via corticocortical projections. Together, our results suggest the motor cortices coordinate sequential bimanual movements through corticocortical pathways.

[Introduction of a new type of mouse forelimb fixator and two types of batch mice moxibustion device].

A newly-developed "Mouse Forelimb Fixator" and two types of "Batch Mice Moxibustion Device" on the basis of our "Mouse Safe and Fast Fixation Board" (developed in 2012) were introduced in the present paper. The Forelimb Fixator inserted into the base part of the apparatus in tenon and mortise style is used to control the mouse's posture with the forelimbs' acupoints fully exposed, and can realize simultaneous fixation of several mice at the same time. By using the mobility of the base of the single-hole moxibustion frame and the magnet, the distance between the acupoint surface and the tip of the ignited moxa stick can be accurately controlled, and several acupoints of different meridians can be simultaneously stimulated at the same time. Utilizing the porous transparent moxibustion board, the Batch Mice Moxibustion Device can meet the requirement of moxibustion at multiple acupoints at the same time. In addition, these devices are convenient in operation, innovative in creativity, save manpower and material resources, and help improve experimental efficiency and research on moxibustion.

A wireless spinal stimulation system for ventral activation of the rat cervical spinal cord.

Electrical stimulation of the cervical spinal cord is gaining traction as a therapy following spinal cord injury; however, it is difficult to target the cervical motor region in a rodent using a non-penetrating stimulus compared with direct placement of intraspinal wire electrodes. Penetrating wire electrodes have been explored in rodent and pig models and, while they have proven beneficial in the injured spinal cord, the negative aspects of spinal parenchymal penetration (e.g., gliosis, neural tissue damage, and obdurate inflammation) are of concern when considering therapeutic potential. We therefore designed a novel approach for epidural stimulation of the rat spinal cord using a wireless stimulation system and ventral electrode array. Our approach allowed for preservation of mobility following surgery and was suitable for long term stimulation strategies in awake, freely functioning animals. Further, electrophysiology mapping of the ventral spinal cord revealed the ventral approach was suitable to target muscle groups of the rat forelimb and, at a single electrode lead position, different stimulation protocols could be applied to achieve unique activation patterns of the muscles of the forelimb.

Disengagement of Motor Cortex during Long-Term Learning Tracks the Performance Level of Learned Movements.

Not all movements require the motor cortex for execution. Intriguingly, dependence on motor cortex of a given movement is not fixed, but instead can dynamically change over the course of long-term learning. For instance, rodent forelimb movements that initially require motor cortex can become independent of the motor cortex after an extended period of training. However, it remains unclear whether long-term neural changes rendering the motor cortex dispensable are a simple function of the training length. To address this issue, we trained mice (both male and female) to perform two distinct forelimb movements, forward versus downward reaches with a joystick, concomitantly over several weeks, and then compared the involvement of the motor cortex between the two movements. Most mice achieved different levels of motor performance between the two movements after long-term training. Of the two movements, the one that achieved higher trial-to-trial consistency (i.e., consistent-direction movement) was significantly less affected by inactivation of motor cortex than the other (i.e., variable-direction movement). Two-photon calcium imaging of motor cortical neurons revealed that the consistent-direction movement activates fewer neurons, producing weaker and less consistent population activity than the variable-direction movement. Together, the motor cortex was less engaged and less necessary for learned movements that achieved higher levels of consistency. Thus, the long-term reorganization of neural circuits that frees the motor cortex from the learned movement is not a mere function of training length. Rather, this reorganization tracks the level of motor performance that the animal achieves during training.SIGNIFICANCE STATEMENT Long-term training of a movement reshapes motor circuits, disengaging motor cortex potentially for automatized execution of the learned movement. Acquiring new motor skills often involves learning of multiple movements (e.g., forehand and backhand strokes when learning tennis), but different movements do not always improve at the same time nor reach the same level of proficiency. Here we showed that the involvement of motor cortex after long-term training differs between similar yet distinct movements that reached different levels of expertise. Motor cortex was less engaged and less necessary for the more proficient movement. Thus, disengagement of motor cortex is not a simple function of training time, but instead tracks the level of expertise of a learned movement.

The role of inflammatory cytokines in anemia and gastrointestinal mucosal injury induced by foot electric stimulation.

Foot electrical stimulation (FES) has been considered as a classic stressor that can disturb homeostasis. Acute anemia was observed in the model induced by FES. The aim of this study was to explore the role of inflammatory cytokines underlying the acute anemia and gastrointestinal (GI) mucosal injury in the FES. Twenty-four male Kunming mice (20 ± 2 g) were randomly divided into control group and experimental group. The mice were placed in a footshock chamber that can generate 0.5 mA electrical impulse periodically for 0.5 h. After the process, red blood cell count, hemoglobin concentration and hematocrit, the levels of corticotropin releasing hormone (CRH) in serum and hypothalamus, and adrenocorticotropic hormone (ACTH) in serum and pituitary were detected separately. In addition, we investigated the expressions of inflammatory cytokines (IL-1, IL-6, TNF-α, iNOS, and IL-10) in the hypothalamus and duodenum by Polymerase Chain Reaction (PCR). Results showed that this FES model induced anemia, increased CRH and ACTH activity in the serum after the FES. Moreover, the expressions of IL-1ß, IL-6, TNF-α, and iNOS were significantly increased following the process, while IL-10 was not activated. These findings suggest that anemia, the inflammatory cytokines in the hypothalamus and duodenum of the mice in the model induced by FES is closely related to GI mucosal injury/bleeding. Taken together, these results underscore the importance of anemia, GI mucosal injury/bleeding and stress, future studies would be needed to translate these findings into the benefit of affected patients.

High-Resolution Focused Ultrasound Neuromodulation Induces Limb-Specific Motor Responses in Mice in Vivo.

Ultrasound can modulate activity in the central nervous system, including the induction of motor responses in rodents. Recent studies investigating ultrasound-induced motor movements have described mostly bilateral limb responses, but quantitative evaluations have failed to reveal lateralization or differences in response characteristics between separate limbs or how specific brain targets dictate distinct limb responses. This study uses high-resolution focused ultrasound (FUS) to elicit motor responses in anesthetized mice in vivo and four-limb electromyography (EMG) to evaluate the latency, duration and power of paired motor responses (n = 1768). The results indicate that FUS generates target-specific differences in electromyographic characteristics and that brain targets separated by as little as 1 mm can modulate the responses in individual limbs differentially. Exploiting these differences may provide a tool for quantifying the susceptibility of underlying neural volumes to FUS, understanding the functioning of the targeted neuroanatomy and aiding in mechanistic studies of this non-invasive neuromodulation technique.

Clinical and morphological justification of the treatment of purulonecrotic lesion in deep structures of limb distal segment in pig: case report / [Justificativa clínica e morfológica do tratamento de lesão purulonecrótica em estruturas profundas do segmento distal de membros em porco: relato de caso]

Surgical pathology of the musculoskeletal system, and in particular the diseases of the limb distal segment in pigs are quite common. Their significant spread leads to economic losses due to culling, compulsory slaughter, short-received pig production and pig crop. The purpose of this work was to reveal clinical and morphological features of limb distal segment diseases in pigs and to study the possibility of preserving their health and productivity. The conservative treatment of purulonecrotic lesions in the deep structures of the limb distal segment in pigs is not promising. It is shown that the best way to treat a given pathology is amputation of a sick limb. The technique of carrying out exarticulation of talus shin consists in separation of soft tissues, capsule and ligaments, ligation of vessels, formation of stump. The postoperative recovery period of the animal body is 25 days.(AU)

A patologia cirúrgica do sistema musculoesquelético e, em particular, as doenças do segmento distal dos membros em suínos são bastante comuns. A sua propagação significativa leva a perdas econômicas devido ao abate seletivo, abate obrigatório, produção de suínos pouco recebida e colheita de suínos. O objetivo deste trabalho foi revelar características clínicas e morfológicas das doenças do segmento distal de membros em suínos e estudar a possibilidade de preservar sua saúde e produtividade. O tratamento conservador das lesões purulonecróticas nas estruturas profundas do segmento distal do membro em porcos não é promissor. Fica estabelecido que a melhor forma de tratar uma determinada patologia é a amputação de um membro doente. A técnica de realizar a exarticulação da canela do talos consiste na separação dos tecidos moles, cápsula e ligamentos, ligadura dos vasos, formação do coto. O período de recuperação pós-operatória do corpo do animal é de 25 dias.(AU)

Granulomatous polyarthritis caused by Talaromyces georgiensis in a dog.

A 6-y-old, 3.5-kg, spayed female Toy Poodle was presented with left forelimb lameness of 2-d duration. Two months before the initial presentation, radiography showed osteolysis of the medial epicondyle of the left humerus, and the left forelimb was amputated. Grossly, the articular villi of the elbow joint were markedly thickened, and the articular cartilage surfaces of the distal humerus and proximal radius had partial erosion. Histologically, granulomatous arthritis and osteomyelitis characterized by the presence of abundant macrophages containing numerous fungi were observed. ITS and ß-tubulin sequences amplified from the isolate from the specimen were 100% and 99% identical to type strain UTHSC D16-145T of Talaromyces georgiensis, respectively. Canine osteoarthritis caused by T. georgiensis has not been reported previously, to our knowledge.

Comparative Enhancement of Motor Function and BDNF Expression Following Different Brain Stimulation Approaches in an Animal Model of Ischemic Stroke.

BACKGROUND: Combinatory intervention such as high-frequency (50-100 Hz) excitatory cortical stimulation (ECS) given concurrently with motor rehabilitative training (RT) improves forelimb function, except in severely impaired animals after stroke. Clinical studies suggest that low-frequency (≤1 Hz) inhibitory cortical stimulation (ICS) may provide an alternative approach to enhance recovery. Currently, the molecular mediators of CS-induced behavioral effects are unknown. Brain-derived neurotrophic factor (BDNF) has been associated with improved recovery and neural remodeling after stroke and thus may be involved in CS-induced behavioral recovery. OBJECTIVE: To investigate whether inhibitory stimulation during RT improves functional recovery of severely impaired rats, following focal cortical ischemia and if this recovery alters BDNF expression (study 1) and depends on BDNF binding to TrkB receptors (study 2). METHODS: Rats underwent ECS + RT, ICS + RT, or noCS + RT treatment daily for 3 weeks following a unilateral ischemic lesion to the motor cortex. Electrode placement for stimulation was either placed ipsilateral (ECS) or contralateral (ICS) to the lesion. After treatment, BDNF expression was measured in cortical tissue samples (study 1). In study 2, the TrkB inhibitor, ANA-12, was injected prior to treatment daily for 21 days. RESULTS: ICS + RT treatment significantly improved impaired forelimb recovery compared with ECS + RT and noCS + RT treatment. CONCLUSION: ICS given concurrently with rehabilitation improves motor recovery in severely impaired animals, and alters cortical BDNF expression; nevertheless, ICS-mediated improvements are not dependent on BDNF binding to TrkB. Conversely, inhibition of TrkB receptors does disrupt motor recovery in ECS + RT treated animals.

Proprioceptive thalamus receiving forelimb and neck muscle spindle inputs via the external cuneate nucleus in the rat.

Proprioceptive signals from body muscles have historically been considered to project to the rostrodorsal shell of the ventrobasal thalamic complex [the ventral posterolateral nucleus (VPL) and ventral posteromedial nucleus (VPM)]. However, we have recently found that proprioception from rat jaw-closing muscle spindles (JCMSs) is conveyed via the supratrigeminal nucleus to the caudo-ventromedial edge of the VPM, but not to the rostrodorsal shell of the VPM. Therefore, proprioception from other body muscles may also project to thalamic regions other than the rostrodorsal shell of the VPL. We thus examined the thalamic projection from the rat external cuneate nucleus (ECu), which receives proprioceptive inputs from forelimb and neck muscles. After injection of anterograde tracer into the ECu, axon terminals were contralaterally labeled in the ventromedial part (VPLvm) of the VPL, but not in the rostrodorsal shell of the VPL. After anterograde tracer injection into the cuneate nucleus (Cu), axon terminals were widely labeled in the contralateral VPL including the VPLvm. In the VPLvm, we electrophysiologically confirmed the proprioceptive inputs responsive to electrical stimulation of the ECu or median nerve and to the pressure of forelimb/neck muscles or wrist flexion. After retrograde tracer injection into the VPLvm, neurons were contralaterally labeled in the ECu and Cu. After retrograde tracer injection into the VPL where no such proprioceptive inputs were recorded, no ECu neurons were labeled. These findings indicate that proprioception from forelimb/neck muscle spindles and JCMSs is somatotopically transmitted to the ventromedial floor of the ventrobasal thalamic complex, but not to its rostrodorsal shell.