Distribution of Midbrain Cholinergic Axons in the Thalamus.

Cholinergic transmission is essential for adaptive behavior and has been suggested to play a central role in the modulation of brain states by means of the modulation of thalamic neurons. Midbrain cholinergic neurons from the pedunculopontine nucleus (PPN) and the laterodorsal tegmental nucleus (LDT) provide dense innervation of the thalamus, but a detailed connectivity mapping is missing. Using conditional tracing of midbrain cholinergic axons in the rat, together with a detailed segmentation of thalamic structures, we show that projections arising in PPN and LDT are topographically organized along the entire extent of the thalamus. PPN cholinergic neurons preferentially innervate thalamic relay structures, whereas LDT cholinergic neurons preferentially target thalamic limbic nuclei. Moreover, both PPN and LDT provide a dense innervation of the intralaminar thalamic nuclei. Notably, we observe a differential synaptic density that functionally dissociates between PPN and LDT innervation. Our results show that midbrain cholinergic neurons innervate virtually all thalamic structures and this innervation is functionally segregated.

Proteomic approach for understanding milder neurotoxicity of Carfilzomib against Bortezomib.

The proteasomal system is responsible for the turnover of damaged proteins. Because of its important functions in oncogenesis, inhibiting the proteasomal system is a promising therapeutic approach for cancer treatment. Bortezomib (BTZ) is the first proteasome inhibitor approved by FDA for clinical applications. However neuropathic side effects are dose limiting for BTZ as many other chemotherapeutic agents. Therefore second-generation proteasome inhibitors have been developed including carfilzomib (CFZ). Aim of the present work was investigating the mechanisms of peripheral neuropathy triggered by the proteasome inhibitor BTZ and comparing the pathways affected by BTZ and CFZ, respectively. Neural stem cells, isolated from the cortex of E14 mouse embryos, were treated with BTZ and CFZ and mass spectrometry was used to compare the global protein pool of treated cells. BTZ was shown to cause more severe cytoskeletal damage, which is crucial in neural cell integrity. Excessive protein carbonylation and actin filament destabilization were also detected following BTZ treatment that was lower following CFZ treatment. Our data on cytoskeletal proteins, chaperone system, and protein oxidation may explain the milder neurotoxic effects of CFZ in clinical applications.

Prelimbic Cortex Deep Brain Stimulation Reduces Binge Size in a Chronic Binge Eating Rat Model.

BACKGROUND: Binge eating (BE) involves the consumption of a large amount of food in a short period of time and a loss of control during the binge episode. It is a key feature of the major subtypes of eating disorders like bulimia nervosa, BE disorder, anorexia nervosa binge/purge type. Alterations in the mesocorticolimbic pathway play a crucial role in its pathophysiology. OBJECTIVES: We hypothesized that BE rats receiving deep brain stimulation (DBS) in the prelimbic cortex, a functional analog of the dorsolateral prefrontal cortex in humans, would have a reduced binge size compared with those receiving sham stimulation. METHODS: Eight male Sprague-Dawley rats were implanted with a DBS electrode in the left prelimbic cortex. A protocol which included limited access to a "sweet-fat" diet was used to achieve a chronic BE state in the rats. After reaching a stable binge size, each rat had undergone sham, low-frequency stimulation (60 Hz), and high-frequency (130 Hz) stimulation for 3 sessions each, and 2 consecutive treatments were separated by at least 2 empty sessions to allow a washout of the effects. A one-way ANOVA was used for the data analysis. RESULTS: Low-frequency (60 Hz) stimulation of the prelimbic cortex significantly reduced the binge size compared to the sham stimulation (p < 0.0001). High-frequency DBS (130 Hz) had no significant influence on this behavior when compared to sham stimulation (p = 0.9). CONCLUSIONS: This study suggests that low-frequency prelimbic cortex stimulation in BE would be useful for correcting prefrontal hypofunction which is strongly associated with BE and addiction pathogenesis.

Extrinsic Sources of Cholinergic Innervation of the Striatal Complex: A Whole-Brain Mapping Analysis.

Acetylcholine in the striatal complex plays an important role in normal behavior and is affected in a number of neurological disorders. Although early studies suggested that acetylcholine in the striatum (STR) is derived almost exclusively from cholinergic interneurons (CIN), recent axonal mapping studies using conditional anterograde tracing have revealed the existence of a prominent direct cholinergic pathway from the pedunculopontine and laterodorsal tegmental nuclei to the dorsal striatum and nucleus accumbens. The identification of the importance of this pathway is essential for creating a complete model of cholinergic modulation in the striatum, and it opens the question as to whether other populations of cholinergic neurons may also contribute to such modulation. Here, using novel viral tracing technologies based on phenotype-specific fluorescent reporter expression in combination with retrograde tracing, we aimed to define other sources of cholinergic innervation of the striatum. Systematic mapping of the projections of all cholinergic structures in the brain (Ch1 to Ch8) by means of conditional tracing of cholinergic axons, revealed that the only extrinsic source of cholinergic innervation arises in the brainstem pedunculopontine and laterodorsal tegmental nuclei. Our results thus place the pedunculopontine and laterodorsal nuclei in a key and exclusive position to provide extrinsic cholinergic modulation of the activity of the striatal systems.