Mice with selective elimination of striatal acetylcholine release are lean, show altered energy homeostasis and changed sleep/wake cycle

  title={Mice with selective elimination of striatal acetylcholine release are lean, show altered energy homeostasis and changed sleep/wake cycle},
  author={Monica S. Guzman and Xavier De Jaeger and Maria Drangova and Marco A. M. Prado and Robert Gros and Vania F. Prado},
  journal={Journal of Neurochemistry},
Cholinergic neurons are known to regulate striatal circuits; however, striatal‐dependent physiological outcomes influenced by acetylcholine (ACh) are still poorly under;?>stood. Here, we used vesicular acetylcholine transporter (VAChT)D2‐Cre‐flox/flox mice, in which we selectively ablated the vesicular acetylcholine transporter in the striatum to dissect the specific roles of striatal ACh in metabolic homeostasis. We report that VAChTD2‐Cre‐flox/flox mice are lean at a young age and maintain… 

Deletion of the vesicular acetylcholine transporter from pedunculopontine/laterodorsal tegmental neurons modifies gait

The results suggest that dysfunction of cholinergic neurons from mesopontine nuclei, which is commonly seen in PD, has causal roles in motor functions and prevention of mesopONTine cholinerg failure may help to prevent/improve postural instability and falls in PD patients.

Cholinergic dysfunction in the dorsal striatum promotes habit formation and maladaptive eating.

It is revealed that loss of acetylcholine leads to a dopamine imbalance in striatal compartments, thereby promoting habits and vulnerability to maladaptive eating in mice.

ChAT–ChR2–EYFP Mice Have Enhanced Motor Endurance But Show Deficits in Attention and Several Additional Cognitive Domains

The studies demonstrate that ChAT–ChR2–EYFP mice show altered cholinergic tone that fundamentally differentiates them from wild-type mice, and suggest that increased VAChT expression may disrupt critical steps in information processing.

Functional dissociation of behavioral effects from acetylcholine and glutamate released from cholinergic striatal interneurons

It is demonstrated that the ability to secrete two different neurotransmitters allows CINs to exert complex modulation of a wide range of behaviors and altered reward‐evoked dopaminergic signalling and behavioral deficits that resemble, but were worse, than those in mice with specific loss of VAChT alone.

Cardiomyocyte‐secreted acetylcholine is required for maintenance of homeostasis in the heart

  • A. RoyWilliam C. Fields M. Prado
  • Biology
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 2013
Cardiomyocyte‐derived ACh is required for maintenance of cardiac homeostasis and regulates critical signaling pathways necessary to maintain normal heart activity, and it is proposed that this non‐neuronal source of ACh boosts parasympathetic cholinergic signaling to counterbalance sympathetic activity regulating multiple aspects of heart physiology.

Deficiency of Meis1, a transcriptional regulator, in mice and worms: Neurochemical and behavioral characterizations with implications in the restless legs syndrome

The data suggest that Meis1 knockout mice have restless legs syndrome‐like motor restlessness and changes in serum ferritin levels, which may be related to dysfunctional dopaminergic and cholinergic systems.

Hyperactivity and attention deficits in mice with decreased levels of stress-inducible phosphoprotein 1 (STIP1)

It is concluded that reduced STIP1 levels can contribute to phenotypes related to ASD, however, future experiments are needed to define whether it is decreased chaperone capacity or impaired prion protein signaling that contributes to these phenotypes.

Investigating the Effect of Vesicular Acetylcholine Transporter Expression on Central and Peripheral Function

The biochemical characteristics of cholinergic neurons following VAChT overexpression were measured and the behaviour phenotype of these animals was evaluated and the effect of lifelong VACh T overexposure on the age-related impairment of hippocampal structure and function was investigated.

Pannexin 1 regulates adipose stromal cell differentiation and fat accumulation

It is concluded that Panx1 plays a key role in adipose stromal cells during the early stages of adipogenic proliferation and differentiation, regulating fat accumulation in vivo.



Novel Strains of Mice Deficient for the Vesicular Acetylcholine Transporter: Insights on Transcriptional Regulation and Control of Locomotor Behavior

The results suggest that release of ACh in the brain is normally required to “turn down” neuronal circuits controlling locomotion, and that VAChT mutant mice present preserved neuromuscular function but altered brain cholinergic function and are hyperactive.

Mice lacking the M3 muscarinic acetylcholine receptor are hypophagic and lean

It is shown that mice deficient in the M3 muscarinic receptor (M3R-/- mice) display a significant decrease in food intake, reduced body weight and peripheral fat deposits, and very low levels of serum leptin and insulin, and there may be a cholinergic pathway that involves M3-receptor-mediated facilitation of food intake at a site downstream of the hypothalamic leptin/melanocortin system and upstream of the MCH system.

Reduced expression of the vesicular acetylcholine transporter causes learning deficits in mice

The memory deficit in object recognition memory observed in VAChT mutant mice could be reversed by cholinesterase inhibitors, suggesting that learning deficits caused by reducedVAChT expression can be ameliorated by restoring ACh levels in the synapse.

The Obesity Susceptibility Gene Carboxypeptidase E Links FoxO1 Signaling in Hypothalamic Pro–opiomelanocortin Neurons with Regulation of Food Intake

It is shown that Cpe expression is downregulated by diet-induced obesity and that FoxO1 deletion offsets the decrease, protecting against weight gain, and raises the possibility of targeting Cpe to develop weight loss medications.

Striatal muscarinic receptor antagonism reduces 24‐h food intake in association with decreased preproenkephalin gene expression

It is hypothesized that cholinergic interneurons assist in translating hypothalamic energy state signals into food‐directed behaviors via their regulation of striatal opioid peptides through their control of enkephalin gene expression.

The vesicular glutamate transporter VGLUT3 synergizes striatal acetylcholine tone

It is proposed that this vesicular synergy between two transmitters is the result of the unbalanced bioenergetics of VAChT, which requires anion co-entry for continuing vesicle filling.

Effects of Feeding and Drinking on Acetylcholine Release in the Nucleus Accumbens, Striatum, and Hippocampus of Freely Behaving Rats

Results suggest a site‐specific increase in ACh release following feeding that cannot be solely attributed to the activation associated with this behavior, and is suggested to be largely neuronal in origin.