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Cognitive and motor deficits in a rodent model of Parkinson’s disease displaying concurrent dopamine and acetylcholine loss
Ostock CY, Conti MM, Larose T, Meadows S, Bishop C (2015) Cognitive and motor deficits in a rodent model of Parkinson’s disease displaying concurrent dopamine and acetylcholine loss. Neuroscience 2015 Abstracts 676.26/D33. Society for Neuroscience, Chicago IL.
Summary: Dopamine (DA) loss in Parkinson’s disease (PD) is frequently accompanied by degeneration of acetylcholine neurons within the basal forebrain (BF) and the pedunculopontine nucleus (PPN). Recently, Ach neurons in these nuclei have been implicated in both the motor and non-motor symptoms of PD. However, few rodent models of PD actually account for Ach loss in both the BF and PPN. Here, we evaluated the effects of concurrent BF and PPN Ach loss alone and in combination with striatal DA loss on motor and cognitive performance in a rat model of PD. Sprague-Dawley rats (N = 44) received bilateral: striatal 6-OHDA lesions to deplete DA (DA-lesioned; n = 14), BF (192 IgG-Saporin) and PPN (anti-ChAT Saporin) saporin lesions to deplete Ach (Ach-lesioned; n = 10), combined 6-OHDA + saporin lesions (dual-lesioned; n = 6) , or sham lesions (n = 14). Following recovery from surgery, rats underwent a battery of motor and cognitive behavioral tests. Results indicated that Ach-lesioned and dual-lesioned rats displayed spatial memory deficits on the Morris Water Maze and Spontaneous Alternation tests. DA and Ach lesions alone impaired stepping for the forepaw adjusting steps and vibrissae-elicited paw placement tests and this deficit was exacerbated in dual-lesioned rats. However, only rats with Ach or dual lesions showed motor deficits on the rotarod tests. Collectively, these findings demonstrate that Ach loss may exacerbate cognitive and motor symptoms in PD and highlight the importance of including Ach loss in preclinical models of PD.
Related Products: 192-IgG-SAP (Cat. #IT-01), Anti-ChAT-SAP (Cat. #IT-42), Saporin (Cat. #PR-01)
Modeling Tourette syndrome pathophysiology through targeted manipulation of striatal interneurons
Pittenger CJ (2015) Modeling Tourette syndrome pathophysiology through targeted manipulation of striatal interneurons. Neuroscience 2015 Abstracts 6.07. Society for Neuroscience, Chicago IL.
Summary: Postmortem studies of Tourette syndrome patients has revealed a reduction in the number of specific striatal interneurons. The authors explored the hypothesis that this neuronal deficit is enough to produce the symptoms of Tourette syndrome in mice. Animals received 90-ng injections of Anti-ChAT-SAP (Cat. #IT-42) into the striatum. Rabbit IgG-SAP (Cat. #IT-35) was used as a control. The data suggest that loss of the striatal interneurons is enough to produce some, but not all, of the symptoms caused by Tourette syndrome.
Related Products: Anti-ChAT-SAP (Cat. #IT-42), Rabbit IgG-SAP (Cat. #IT-35)
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Featured Article: A specific immunotoxin elucidates a causal role of striatal cholinergic system in behavioral flexibility
Aoki S, Wickens JR (2015) Featured Article: A specific immunotoxin elucidates a causal role of striatal cholinergic system in behavioral flexibility. Targeting Trends 16(4)
Related Products: Anti-ChAT-SAP (Cat. #IT-42)
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Role of striatal cholinergic interneurons in set-shifting in the rat.
Aoki S, Liu A, Zucca A, Zucca S, Wickens J (2015) Role of striatal cholinergic interneurons in set-shifting in the rat. J Neurosci 35:9424-9431. doi: 10.1523/JNEUROSCI.0490-15.2015
Summary: The authors examined the role that cholinergic interneurons in the striatum play in a process called strategy set-shifting, where an attentional shift is required. Rats received bilateral injections of Anti-ChAT-SAP (Cat. #IT-42) into either the dorsomedial striatum or ventral striatum (500 ng total). Initial task learning was unaffected by either lesion. Lesioned animals displayed set-shifting deficits, and the deficit characteristics depended on the location of the lesion.
Related Products: Anti-ChAT-SAP (Cat. #IT-42)
Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome.
Xu M, Kobets A, Du J, Lennington J, Li L, Banasr M, Duman R, Vaccarino F, DiLeone R, Pittenger C (2015) Targeted ablation of cholinergic interneurons in the dorsolateral striatum produces behavioral manifestations of Tourette syndrome. Proc Natl Acad Sci U S A 112:893-898. doi: 10.1073/pnas.1419533112
Summary: Postmortem studies of Tourette syndrome patients has revealed a reduction in the number of specific striatal interneurons. The authors explored the hypothesis that this neuronal deficit is enough to produce the symptoms of Tourette syndrome in mice. Animals received 90-ng injections of Anti-ChAT-SAP (Cat. #IT-42) into the striatum. Rabbit IgG-SAP (Cat. #IT-35) was used as a control. The data suggest that loss of the striatal interneurons is enough to produce some, but not all, of the symptoms caused by Tourette syndrome.
Related Products: Anti-ChAT-SAP (Cat. #IT-42), Rabbit IgG-SAP (Cat. #IT-35)
Featured Article: Impairments in gait, posture and complex movement control in rats modeling the multi-system, cholinergic-dopaminergic losses in Parkinson’s Disease
Kucinski A (2015) Featured Article: Impairments in gait, posture and complex movement control in rats modeling the multi-system, cholinergic-dopaminergic losses in Parkinson’s Disease. Targeting Trends 16(1)
Related Products: 192-IgG-SAP (Cat. #IT-01), Anti-ChAT-SAP (Cat. #IT-42)
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Impairments in gait, posture and complex movement control in rats modeling the multi-system, cholinergic-dopaminergic losses in PD.
Phillips K, Kucinski A, Albin R, Sarter M (2014) Impairments in gait, posture and complex movement control in rats modeling the multi-system, cholinergic-dopaminergic losses in PD. Neuroscience 2014 Abstracts 692.21. Society for Neuroscience, Washington, DC.
Summary: In addition to striatal dopamine loss, degeneration of cholinergic neurons in the basal forebrain (BF) and the brainstem pedunculopontine nucleus (PPN) were documented in patients with Parkinson’s disease (PD). Loss of cholinergic projections to cortical, thalamic and midbrain regions have been associated with impairments in gait and postural control and a propensity for falls. We previously demonstrated that loss of cortical cholinergic inputs and the resulting impairments in attentional control ‘unmask’ gait and postural risk factors and thus yielded falls in rats with striatal dopamine loss (Kucinski et al., 2013). For this research we developed a new behavior task for the assessment of gait, postural control, and fall propensity (Michigan Complex Motor Control Task; MCMCT). Here, to determine the contributions of the PPN cholinergic projection system to complex movement control, we also lesioned the cholinergic pars compacta (posterior) division of the PPN by infusing anti-ChAT saporin-coupled immunotoxin. Rats received these lesions either in combination with BF cholinergic (192-IgG-saporin) or dorsomedial striatal dopamine loss (6-OHDA), or all three lesions together (“triples”). MCMCT performance by triples was characterized by more falls than in rats with just PPN lesions, PPN plus striatal dopamine loss, or rats with loss of both BF and PPN cholinergic neurons. High fall rates in triples persisted throughout the 20-day MCMCT testing sequence, indicating that daily practice did not improve the interactions between loss of attentional control and gait and postural deficits that underlie falls. Interestingly, combined loss of BF and PPN cholinergic neurons increased falls relative to controls and single lesions, suggesting that ascending cholinergic PPN loss sufficiently dysregulates striatal dopamine input for BF cholinergic cell loss to ‘unmask’ the impact of the former on striatal dysfunction. Finally, PPN cholinergic cell loss resulted in ballistic postural (recovery) movements and slip-triggered switches to asymmetrical gait. Such behavior was previously observed in rats after electrolytic lesions of the PPN region, considered a model of “Parkinsonian festination” (Cheng et al., 1981) and it may assist in maintaining balance by stabilizing the center of gravity. Collectively, our findings support the hypothesis that PPN cholinergic projections contribute to the mediation of gait symmetry and postural control, and when lesioned in combination with forebrain cholinergic and dopaminergic system, results in profound impairments in the control of complex movements. This research was supported by the Michael J. Fox Foundation.
Related Products: Anti-ChAT-SAP (Cat. #IT-42)
ATS Poster of the Year Winner. Read the featured article in Targeting Trends.
Reduction in cholinergic interneuron density in the nucleus accumbens attenuates local extracellular dopamine release in response to stress or amphetamine.
Laplante F, Dufresne MM, Ouboudinar J, Ochoa-Sanchez R, Sullivan RM (2013) Reduction in cholinergic interneuron density in the nucleus accumbens attenuates local extracellular dopamine release in response to stress or amphetamine. Synapse 67(1):21-29. doi: 10.1002/syn.21612
Summary: The authors examined whether excessive dopamine neurotransmission in the mesolimbic system is due to higher levels of presynaptic or postsynaptic dopamine. Rats received 250-ng bilateral injections of anti-ChAT-SAP (Cat. #IT-42) into the nucleus accumbens. Rabbit IgG-SAP (Cat. #IT-35) was used as a control. The data suggest that reduction of cholinergic interneurons in the nucleus accumbens suppresses presynaptic dopamine release.
Related Products: Anti-ChAT-SAP (Cat. #IT-42), Rabbit IgG-SAP (Cat. #IT-35)
Featured Article: Role of cholinergic neurons in the nucleus accumbens and their involvement in schizophrenic pathology
LaPlante F (2013) Featured Article: Role of cholinergic neurons in the nucleus accumbens and their involvement in schizophrenic pathology. Targeting Trends 14(1)
Related Products: Anti-ChAT-SAP (Cat. #IT-42), Rabbit IgG-SAP (Cat. #IT-35)
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Cholinergic depletion in nucleus accumbens impairs mesocortical dopamine activation and cognitive function in rats.
Laplante F, Zhang ZW, Huppe-Gourgues F, Dufresne MM, Vaucher E, Sullivan RM (2012) Cholinergic depletion in nucleus accumbens impairs mesocortical dopamine activation and cognitive function in rats. Neuropharmacology 63(6):1075-1084. doi: 10.1016/j.neuropharm.2012.07.033
Summary: Current thought is that loss of cholinergic function in the nucleus accumbens (N.Acc) is associated with schizophrenia. This deficit is accompanied by low dopaminergic activity in the prefrontal area, which adversely affects working memory. Rats received bilateral injections totaling 500 ng of anti-ChAT-SAP (Cat. #IT-42) into the N.Acc; rabbit IgG-SAP (Cat. #IT-35) was used as a control. Lesioned animals had markedly reduced mesocortical dopamine activation, which corresponded with cognitive impairments. The data suggest that loss of cholinergic neurons in the N.Acc causes loss of dopamine function in the mesocorticolimbic system.
Related Products: Anti-ChAT-SAP (Cat. #IT-42), Rabbit IgG-SAP (Cat. #IT-35)