Separation of Channels Subserving Approach and Avoidance/Escape at the Level of the Basal Ganglia and Related Brainstem Structures.

The basal ganglia have the key function of directing our behavior in the context of events from our environment and/or our internal state. This function relies on afferents targeting the main input structures of the basal ganglia, entering bids for action selection at the level of the striatum or sig- nals for behavioral interruption at the level of the subthalamic nucleus, with behavioral reselection facilitated by dopamine signaling. Numerous experiments have studied action selection in relation to inputs from the cerebral cortex. However, less is known about the anatomical and functional link between the basal ganglia and the brainstem. In this review, we describe how brainstem structures also project to the main input structures of the basal ganglia, namely the striatum, the subthalamic nucleus and midbrain dopaminergic neurons, in the context of approach and avoidance (including escape from threat), two fundamental, mutually exclusive behavioral choices in an animal's repertoire in which the brainstem is strongly involved. We focus on three particularly well-described loci involved in approach and avoidance, namely the superior colliculus, the parabrachial nucleus and the periaqueductal grey nucleus. We consider what is known about how these structures are related to the basal ganglia, focusing on their projections toward the striatum, dopaminergic neurons and subthalamic nucleus, and explore the functional consequences of those interactions.

Altered parabrachial nucleus nociceptive processing may underlie central pain in Parkinson's disease.

The presence of central neuropathic pain in Parkinson's disease suggests that the brain circuits that allow us to process pain could be dysfunctional in the disorder. However, there is to date no clear pathophysiological mechanism to explain these symptoms. In this work, we present evidence that the dysfunction of the subthalamic nucleus and/or substantia nigra pars reticulata may impact nociceptive processing in the parabrachial nucleus (PBN), a low level primary nociceptive structure in the brainstem, and induce a cellular and molecular neuro-adaptation in this structure. In rat models of Parkinson's disease with a partial dopaminergic lesion in the substantia nigra compacta, we found that the substantia nigra reticulata showed enhanced nociceptive responses. Such responses were less impacted in the subthalamic nucleus. A total dopaminergic lesion produced an increase in the nociceptive responses as well as an increase of the firing rate in both structures. In the PBN, inhibited nociceptive responses and increased expression of GABAA receptors were found following a total dopaminergic lesion. However, neuro-adaptations at the level of dendritic spine density and post-synaptic density were found in both dopaminergic lesion groups. These results suggest that the molecular changes within the PBN following a larger dopaminergic lesion, such as increased GABAA expression, is a key mechanism to produce nociceptive processing impairment, whilst other changes may protect function after smaller dopaminergic lesions. We also propose that these neuro-adaptations follow increased inhibitory tone from the substantia nigra pars reticulata and may represent the mechanism generating central neuropathic pain in Parkinson's disease.

The Subthalamic Nucleus: A Hub for Sensory Control via Short Three- Lateral Loop Connections with the Brainstem?

The subthalamic nucleus (STN) is classically subdivided into sensori-motor, associative and limbic regions, which is consistent with the involvement of this structure in not only motor control, but also in cognitive and emotional tasks. However, the function of the sensory inputs to the STN's sensori-motor territory is comparatively less well explored, although sensory responses have been reported in this structure. There is still a paucity of information regarding the characteristics of that subdivision and its potential functional role in basal ganglia processing and more widely in associated networks. In this perspective paper, we summarize the type of sensory stimuli that have been reported to activate the STN, and describe the complex sensory properties of the STN and its anatomical link to a sensory network involving the brainstem, characterized in our recent work. Analyzing the sensory input to the STN led us to suggest the existence of previously unreported threelateral subcortical loops between the basal ganglia and the brainstem which do not involve the cortex. Anatomically, these loops closely link the STN, the substantia nigra pars reticulata and various structures from the brainstem such as the superior colliculus and the parabrachial nucleus. We also discuss the potential role of the STN in the control of sensory activity in the brainstem and its possible contribution to favoring sensory habituation or sensitization over brainstem structures to optimize the best selection of action at a given time.

Glioma Associated Microglia/Macrophages Distribution is Conserved in Glioblastoma Regrowth: A Morphometric Study.

We compared the morphological aspect of glioblastoma-associated microglia/macrophages cells in 15 paired recurrent glioblastomas to check the ability of glioblastoma to recreate its microenvironment. The absolute number of GAMs is lower in normal tissue (21/mm2) than in the isolated tumor cells area (100-112/mm2) than in the solid tumor area (212-220/mm2) (p < 0.01). The morphology of GAMs remained the same in each tumor area with a reduced covered area by cell processes (196 to 216/mm2) than in normal tissue (708/mm2) (p < 0.01). In paired tumors, GAMs morphology remained the same in successive resections and was not modified by the treatments.

A basal ganglia-like cortical-amygdalar-hypothalamic network mediates feeding behavior.

The insular cortex (INS) is extensively connected to the central nucleus of the amygdala (CEA), and both regions send convergent projections into the caudal lateral hypothalamus (LHA) encompassing the parasubthalamic nucleus (PSTN). However, the organization of the network between these structures has not been clearly delineated in the literature, although there has been an upsurge in functional studies related to these structures, especially with regard to the cognitive and psychopathological control of feeding. We conducted tract-tracing experiments from the INS and observed a pathway to the PSTN region that runs parallel to the canonical hyperdirect pathway from the isocortex to the subthalamic nucleus (STN) adjacent to the PSTN. In addition, an indirect pathway with a relay in the central amygdala was also observed that is similar in its structure to the classic indirect pathway of the basal ganglia that also targets the STN. C-Fos experiments showed that the PSTN complex reacts to neophobia and sickness induced by lipopolysaccharide or cisplatin. Chemogenetic (designer receptors exclusively activated by designer drugs [DREADD]) inhibition of tachykininergic neurons (Tac1) in the PSTN revealed that this nucleus gates a stop "no-eat" signal to refrain from feeding when the animal is subjected to sickness or exposed to a previously unknown source of food. Therefore, our anatomical findings in rats and mice indicate that the INS-PSTN network is organized in a similar manner as the hyperdirect and indirect basal ganglia circuitry. Functionally, the PSTN is involved in gating feeding behavior, which is conceptually homologous to the motor no-go response of the adjacent STN.

Revealing a novel nociceptive network that links the subthalamic nucleus to pain processing.

Pain is a prevalent symptom of Parkinson's disease, and is effectively treated by deep brain stimulation of the subthalamic nucleus (STN). However, the link between pain and the STN remains unclear. In the present work, using in vivo electrophysiology in rats, we report that STN neurons exhibit complex tonic and phasic responses to noxious stimuli. We also show that nociception is altered following lesions of the STN, and characterize the role of the superior colliculus and the parabrachial nucleus in the transmission of nociceptive information to the STN, physiologically from both structures and anatomically in the case of the parabrachial nucleus. We show that STN nociceptive responses are abnormal in a rat model of PD, suggesting their dependence on the integrity of the nigrostriatal dopaminergic system. The STN-linked nociceptive network that we reveal is likely to be of considerable clinical importance in neurological diseases involving a dysfunction of the basal ganglia.