Electrical stimulation of the motor cortex enhances progenitor cell migration in the adult rat brain.

Clinical and preclinical investigations suggest that epidural stimulation of the motor cortex (MC) can improve stroke-induced neurological deficits. The mechanisms involved in stimulation-induced recovery are not well understood and might involve neurogenesis-related processes. Here, we addressed the question whether MC stimulation influences processes of migration and differentiation of neuronal progenitor cells in vivo. Epidural stimulation electrodes were implanted at the level of the MC in rats, and electrical current was applied for a period of 1 month. Increased cell proliferation was observed in the subventricular zone (SVZ). We also found evidences for enhanced cell migration toward the source of current, a process known as electrotaxis. Some of these cells expressed the neuronal marker, NeuN. In addition, our results indicate that MC stimulation enhances neuronal activity of the dorsal raphe nucleus, leading to an increase in the expression of 5-hydroxytryptamine in the SVZ. It is known that such an increase can promote formation of new cells in the SVZ. Our findings suggest that epidural MC stimulation influences neurogenesis-related processes in animal models.

5-HT1A receptor agonism in the basolateral amygdala increases mutual-reward choices in rats.

Rats show mutual-reward preferences, i.e., they prefer options that result in a reward for both themselves and a conspecific partner to options that result in a reward for themselves, but not for the partner. In a previous study, we have shown that lesions of the basolateral amygdala (BLA) reduced choices for mutual rewards. Here, we aimed to explore the role of 5-HT1A receptors within the BLA in mutual-reward choices. Rats received daily injections of either 50 or 25 ng of the 5-HT1A receptor agonist 8-OH-DPAT or a vehicle solution into the BLA and mutual-reward choices were measured in a rodent prosocial choice task. Compared to vehicle injections, 8-OH-DPAT significantly increased mutual-reward choices when a conspecific was present. By contrast, mutual-reward choices were significantly reduced by 8-OH-DPAT injections in the presence of a toy rat. The effect of 8-OH-DPAT injections was statistically significant during the expression, but not during learning of mutual-reward behavior, although an influence of 8-OH-DPAT injections on learning could not be excluded. There were no differences between 8-OH-DPAT-treated and vehicle-treated rats in general reward learning, behavioral flexibility, locomotion or anxiety. In this study, we have shown that repeated injections of the 5-HT1A receptor agonist 8-OH-DPAT have the potential to increase mutual-reward choices in a social setting without affecting other behavioral parameters.

Lesions of the rat basolateral amygdala reduce the behavioral response to ultrasonic vocalizations.

Rats emit vocalizations in the ultrasonic range (ultrasonic vocalizations; USVs), of which 50-kHz USVs could communicate positive affective states and induce approach behavior in conspecifics, whereas 22-kHz USVs might signal negative affective states and potential threats. Listening to 50-kHz USVs can be rewarding, but it is unknown which brain mechanisms are responsible for the assignment of reinforcing value to 50-kHz USVs . The behavioral responses induced by listening to 22-kHz USVs are heterogeneous and need further characterization. The amygdala is a region relevant for social perception, behavior and reward. Here, we tested the hypothesis that the basolateral amygdala (BLA) plays a causal role in motivating behavioral responses to 50-kHz and 22-kHz USVs. Rats with lesions of the BLA or sham lesions were repeatedly exposed to playback of either 50-kHz or 22-kHz USVs in a radial maze. Compared to sham rats, BLA-lesioned rats spent less time in the arms close to the USV speaker during playback of both 50-kHz or 22-kHz USVs. This difference in behavior was not due to impaired motor or general auditory abilities, indicating that BLA lesions selectively reduced the responsiveness to stimuli with social significance. This finding provides further support for the hypothesis that the BLA plays an important role in motivating approach behavior to social reinforcers.

Beyond Emotions: Oscillations of the Amygdala and Their Implications for Electrical Neuromodulation.

The amygdala is a structure involved in emotions, fear, learning and memory and is highly interconnected with other brain regions, for example the motor cortex and the basal ganglia that are often targets of treatments involving electrical stimulation. Deep brain stimulation of the basal ganglia is successfully used to treat movement disorders, but can carry along non-motor side effects. The origin of these non-motor side effects is not fully understood yet, but might be altered oscillatory communication between specific motor areas and the amygdala. Oscillations in various frequency bands have been detected in the amygdala during cognitive and emotional tasks, which can couple with oscillations in cortical regions or the hippocampus. However, data on oscillatory coupling between the amygdala and motor areas are still lacking. This review provides a summary of oscillation frequencies measured in the amygdala and their possible functional relevance in different species, followed by evidence for connectivity between the amygdala and motor areas, such as the basal ganglia and the motor cortex. We hypothesize that the amygdala could communicate with motor areas through coherence of low frequency bands in the theta-alpha range. Furthermore, we discuss a potential role of the amygdala in therapeutic approaches based on electrical stimulation.

Evaluating rodent motor functions: Which tests to choose?

Damage to the motor cortex induced by stroke or traumatic brain injury (TBI) can result in chronic motor deficits. For the development and improvement of therapies, animal models which possess symptoms comparable to the clinical population are used. However, the use of experimental animals raises valid ethical and methodological concerns. To decrease discomfort by experimental procedures and to increase the quality of results, non-invasive and sensitive rodent motor tests are needed. A broad variety of rodent motor tests are available to determine deficits after stroke or TBI. The current review describes and evaluates motor tests that fall into three categories: Tests to evaluate fine motor skills and grip strength, tests for gait and inter-limb coordination and neurological deficit scores. In this review, we share our thoughts on standardized data presentation to increase data comparability between studies. We also critically evaluate current methods and provide recommendations for choosing the best behavioral test for a new research line.

Long-Term Motor Deficits after Controlled Cortical Impact in Rats Can Be Detected by Fine Motor Skill Tests but Not by Automated Gait Analysis.

Animal models with constant, long-lasting motor deficits together with the right tests to assess behavioral abnormalities are needed to study the effectiveness of potential therapies to restore motor functions. In the current study, controlled cortical impact (CCI) was applied in rats to induce damage to the forelimb area of the motor cortex and the dorsal striatum. Motor behavior was assessed before and after CCI, using fine motor skill tests such as the adhesive removal test, the cylinder test, and the Montoya staircase test as well as the automated gait analysis system CatWalk XT over a 6 week period. CCI caused a variety of unilateral motor deficits, which were characterized in detail by using the selected fine motor skill tests. In striking contrast to previous studies on CCI in mice, neither forelimb impairments, nor general changes in gait, were detected with the CatWalk XT. These data suggest that the adhesive removal test, the cylinder test, and the Montoya staircase test are the methods of choice to detect long-term unilateral motor deficits in rats after CCI, whereas the use of automated gait analysis systems might not be suitable to measure these behavioral deviations.

Fornix deep brain stimulation induced long-term spatial memory independent of hippocampal neurogenesis.

Deep brain stimulation (DBS) is an established symptomatic treatment modality for movement disorders and constitutes an emerging therapeutic approach for the treatment of memory impairment. In line with this, fornix DBS has shown to ameliorate cognitive decline associated with dementia. Nonetheless, mechanisms mediating clinical effects in demented patients or patients with other neurological disorders are largely unknown. There is evidence that DBS is able to modulate neurophysiological activity in targeted brain regions. We therefore hypothesized that DBS might be able to influence cognitive function via activity-dependent regulation of hippocampal neurogenesis. Using stimulation parameters, which were validated to restore memory loss in a previous behavioral study, we here assessed long-term effects of fornix DBS. To do so, we injected the thymidine analog, 5-bromo-2'-deoxyuridine (BrdU), after DBS and perfused the animals 6.5 weeks later. A week prior to perfusion, memory performance was assessed in the water maze. We found that acute stimulation of the fornix improved spatial memory performance in the water maze when the probe trial was performed 1 h after the last training session. However, no evidence for stimulation-induced neurogenesis was found in fornix DBS rats when compared to sham. Our results suggest that fornix DBS improves memory functions independent of hippocampal neurogenesis, possibly through other mechanisms such as synaptic plasticity and acute neurotransmitter release.

Motor cortex stimulation does not lead to functional recovery after experimental cortical injury in rats.

BACKGROUND: Motor impairments are among the major complications that develop after cortical damage caused by either stroke or traumatic brain injury. Motor cortex stimulation (MCS) can improve motor functions in animal models of stroke by inducing neuroplasticity. OBJECTIVE: In the current study, the therapeutic effect of chronic MCS was assessed in a rat model of severe cortical damage. METHODS: A controlled cortical impact (CCI) was applied to the forelimb area of the motor cortex followed by implantation of a flat electrode covering the lesioned area. Forelimb function was assessed using the Montoya staircase test and the cylinder test before and after a period of chronic MCS. Furthermore, the effect of MCS on tissue metabolism and lesion size was measured using [18F]-fluorodesoxyglucose (FDG) µPET scanning. RESULTS: CCI caused a considerable lesion at the level of the motor cortex and dorsal striatum together with a long-lasting behavioral phenotype of forelimb impairment. However, MCS applied to the CCI lesion did not lead to any improvement in limb functioning when compared to non-stimulated control rats. Also, MCS neither changed lesion size nor distribution of FDG. CONCLUSION: The use of MCS as a standalone treatment did not improve motor impairments in a rat model of severe cortical damage using our specific treatment modalities.

Deep Brain Stimulation of the Rat Subthalamic Nucleus Induced Inhibition of Median Raphe Serotonergic and Dopaminergic Neurotransmission.

AIM: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) relieves motor dysfunction in advanced Parkinson's disease (PD). However, STN DBS treated patients can experience unpleasant and debilitating psychiatric side effects such as depression and impulsivity. The neural basis of these psychiatric effects has been linked to a dysfunction of 5-hydroxytryptamine (5-HT, serotonin) neurotransmission. STN DBS inhibited activity of 5-HT cell bodies in the dorsal raphe nucleus (DRN). Another important 5-HT source is located in the median raphe nucleus (MRN), which also contains a population of dopamine neurons. The effects of STN DBS on the MRN are unknown. Here, we test the hypothesis that STN DBS reduces 5-HT and dopaminergic function in the MRN, which may contribute to the psychiatric side effects of STN stimulation. MATERIAL AND METHODS: Bilateral STN DBS was applied in a freely moving rat model. Following STN DBS, rats were sacrificed and the brains were processed for c-Fos, 5-HT and tyrosine hydroxylase (TH) immunohistochemistry. RESULTS: We found that STN DBS significantly lowered c-Fos expression compared to non-stimulated controls indicating reduced neuronal activity. Moreover, the mean optical density values of 5-HT and TH cells in the MRN was significantly lower compared to controls. CONCLUSION: These results show that STN DBS inhibits 5-HT and dopamine neurotransmission in the MRN.

In vitro and in vivo neuronal electrotaxis: a potential mechanism for restoration?

Electrical brain stimulation used to treat a variety of neurological and psychiatric diseases is entering a new period. The technique is well established and the potential complications are well known and generally manageable. Recent studies demonstrated that electrical fields (EFs) can enhance neuroplasticity-related processes. EFs applied in the physiological range induce migration of different neural cell types from different species in vitro. There are some evidences that also the speed and directedness of cell migration are enhanced by EFs. However, it is still unclear how electrical signals from the extracellular space are translated into intracellular actions resulting in the so-called electrotaxis phenomenon. Here, we aim to provide a comprehensive review of the data on responses of cells to electrical stimulation and the relation to functional recovery.