Input of sensory, limbic, basal ganglia and pallial/cortical information into the ventral/lateral habenula: Functional principles in anuran amphibians.

The habenula - a phylogenetically old brain structure present in all vertebrates - is involved in pain processing, reproductive behaviors, sleep-wake cycles, stress responses, reward, and learning. We performed intra- and extracellular recordings of ventral habenula (VHb) neurons in the isolated brain of anurans and revealed similar cell and response properties to those reported for the lateral habenula of mammals. We identified tonic regular, tonic irregular, rhythmic firing, and silent VHb neurons. Transitions between these firing patterns were observed during spontaneous activity. Electrical stimulation of various brain areas demonstrated VHb input of auditory, optic, limbic, basal ganglia, and pallial information. This resulted in three different response behaviors in VHb neurons: excitation, inhibition, or alternating facilitation and suppression of neuronal activity. Spontaneously changing activity patterns were observed to modulate, reset, or suppress the response behavior of VHb neurons, indicating a gating mechanism. This could be a network status or context dependent selection mechanism for which information are transmitted to task relevant brain areas (i.e., sensory system, limbic system, basal ganglia). Furthermore, alternating facilitation and suppression sequences upon auditory nerve stimulation correlated positively fictive motor activities recorded via the compound potential of the vagal nerve. Stimulation of the auditory nerve or the habenula led to facilitation, suppression, or alternating facilitation and suppression of neuronal activity in putative dopaminergic neurons. Due to complex habenula feedback loops with basal ganglia, limbic, and sensory systems, the habenula involvement in a variety of functions might therefore be explained by a modulatory effect on a task-relevant input stream.

Refinement of the dopaminergic system of anuran amphibians based on connectivity with habenula, basal ganglia, limbic system, pallium, and spinal cord.

Whereas our understanding of the dopaminergic system in mammals allows for a distinction between ventral tegmental area (VTA) and substantia nigra pars compacta (SNc), no clear evidence for separate structures in anamniotes has been presented to date. To broaden the insight into the organization and regulation of neuromodulatory systems in anuran amphibians, tracing and immunohistochemical investigations were performed in the Oriental fire-bellied toad, Bombina orientalis. Topographically organized catecholaminergic "nigrostriatal," "mesolimbic," "mesocortical," and spinal cord projections arising from the posterior tubercle and mesencephalic tegmentum were identified. We compared these results with published data from lampreys, chondrichthyes, teleosts, amphibians, reptiles, birds, and mammals. Based on the pattern of organization, as well as the differential innervation by the habenular nuclei, domains gradually comparable to the mammalian paranigral VTA, ventral tier of the SNc, interfascicular nucleus of the VTA, and supramamillary/retromamillary area were identified. Additionally, we could demonstrate topographic separate populations of habenula neurons projecting via a direct excitatory or indirect GABAergic pathway onto the catecholaminergic VTA/SNc homologs and serotonergic raphe nuclei. The indirect GABAergic habenula pathway derives from neurons in the superficial mamillary area, which in terms of its connectivity and chemoarchitecture resembles the mammalian rostromedial tegmental nucleus. These results demonstrate a much more elaborate interconnection principle of the anuran dopaminergic system than previously assumed. Based on the data presented it seems that most features of the dopaminergic system of amniotes had already evolved when the amphibian line of evolution diverged from that leading up to mammals, reptiles, and birds.

The habenula as an evolutionary conserved link between basal ganglia, limbic, and sensory systems-A phylogenetic comparison based on anuran amphibians.

Based on anatomical and functional data, the habenula-a phylogenetically old brain structure present in all vertebrates-takes part in the integration of limbic, sensory, and basal ganglia information to guide effective response strategies appropriate to environmental conditions. In the present study, we investigated the connections of the habenular nuclei of the oriental fire-bellied toad, Bombina orientalis, and compared them with published data from lampreys, chondrichthyes, teleosts, reptiles, birds, and mammals. During phylogenetic development, the primordial habenula circuitry underwent various evolutionary adaptations and in the tetrapod line, the circuit complexity increased. The habenula circuitry of anuran amphibians, decedents of the first land-living tetrapods, seem to exhibit a mix of ancient as well as modern features. The anuran medial and lateral habenula homologs receive differential input from the septum, nucleus of the diagonal band of Broca, preoptic area, hypothalamus, rostral pallium, nucleus accumbens, ventral pallidum, and bed nucleus of the stria terminalis. Additional input arises from a border region in the ventral prethalamus, here discussed as a putative homolog of the entopeduncular nucleus of rodents. The habenular subnuclei also differentially innervate the interpeduncular nucleus, raphe nuclei, substantia nigra pars compacta and ventral tegmental area homologs, superficial mamillary area, laterodorsal tegmental nucleus, locus coeruleus, inferior and superior colliculus homologs, hypothalamus, preoptic area, septum, nucleus of the diagonal band of Broca, and main olfactory bulb. It seems likely that the main connectivity between the habenula and the basal ganglia, limbic, and sensory systems was already present in the common tetrapod ancestor.

Transcranial direct current stimulation accelerates recovery of function, induces neurogenesis and recruits oligodendrocyte precursors in a rat model of stroke.

BACKGROUND: Clinical data suggest that transcranial direct current stimulation (tDCS) may be used to facilitate rehabilitation after stroke. However, data are inconsistent and the neurobiological mechanisms underlying tDCS remain poorly explored, impeding its implementation into clinical routine. In the healthy rat brain, tDCS affects neural stem cells (NSC) and microglia. We here investigated whether tDCS applied after stroke also beneficially affects these cells, which are known to be involved in regeneration and repair. METHODS: Focal cerebral ischemia was induced in rats by transient occlusion of the middle cerebral artery. Twenty-eight animals with comparable infarcts, as judged by magnetic resonance imaging, were randomized to receive a multi-session paradigm of either cathodal, anodal, or sham tDCS. Behaviorally, recovery of motor function was assessed by Catwalk. Proliferation in the NSC niches was monitored by Positron-Emission-Tomography (PET) employing the radiotracer 3'-deoxy-3'-[(18)F]fluoro-l-thymidine ([(18)F]FLT). Microglia activation was depicted with [(11)C]PK11195-PET. In addition, immunohistochemical analyses were used to quantify neuroblasts, oligodendrocyte precursors, and activation and polarization of microglia. RESULTS: Anodal and cathodal tDCS both accelerated functional recovery, though affecting different aspects of motor function. Likewise, tDCS induced neurogenesis independently of polarity, while only cathodal tDCS recruited oligodendrocyte precursors towards the lesion. Moreover, cathodal stimulation preferably supported M1-polarization of microglia. CONCLUSIONS: TDCS acts through multifaceted mechanisms that far exceed its primary neurophysiological effects, encompassing proliferation and migration of stem cells, their neuronal differentiation, and modulation of microglia responses.