Oliveira LM, Falquetto B, Moreira TS, Takakura AC (2018) Orexinergic neurons are involved in the chemosensory control of breathing during the dark phase in a Parkinson’s disease model. Exp Neurol 309:107-118. doi: 10.1016/j.expneurol.2018.08.004

Objective: To determine the involvement of orexin cells from the lateral hypothalamus/perifornical area (LH/PeF) on breathing.

Summary: The degeneration of orexinergic neurons in this model of PD can be related to impaired chemoreceptor function in the dark phase.

Usage: For lesions of LH/PeF, two injections of Orexin-B-SAP or Rabbit IgG-SAP (100 ng/μl) were made into the lateral hypothalamus / perifornical area (LH/PeF).

Related Products: Orexin-B-SAP (Cat. #IT-20), Rabbit IgG-SAP (Cat. #IT-35)

Ermine CM, Wright JL, Frausin S, Kauhausen JA, Parish CL, Stanic D, Thompson LH (2018) Modelling the dopamine and noradrenergic cell loss that occurs in Parkinson’s disease and the impact on hippocampal neurogenesis. Hippocampus 28(5):327-337. doi: 10.1002/hipo.22835

Objective: The mechanisms underlying reduced neurogenesis in Parkinson’s Disease (PD) are not well established. The authors tested the hypothesis that noradrenergic and dopaminergic depletion, as occurs in PD, impairs hippocampal neurogenesis.

Summary: Mechanisms of neurotransmitter-based regulation of cognition and hippocampal neurogenesis may well overlap under certain conditions but the present results do not suggest a simple relationship associated with the degeneration of the two most prominently affected transmitter systems in PD.

Usage: Rats received 1 mcg Anti-DBH-SAP icv.

Related Products: Anti-DBH-SAP (Cat. #IT-03)

Oliveira LM, Moreira TS, Takakura AC (2018) Raphe pallidus is not important to central chemoreception in a rat model of Parkinson’s disease. Neuroscience 369:350-362. doi: 10.1016/j.neuroscience.2017.11.038

Objective: To investigate if serotonin-expressing neurons in the Raphe pallidus/parapyramidal region (RPa/PPy) are also involved in the modulation of breathing during central chemoreception activation in a PD animal model.

Related Products: Anti-SERT-SAP (Cat. #IT-23), Saporin (Cat. #PR-01)

Falquetto B, Oliveira LM, Moreira TS, Takakura AC (2017) Role of orexinergic neurons in the chemosensory control of breathing in a Parkinson’s disease model. Neuroscience 2017 Abstracts 779.08 / HH1. Society for Neuroscience, Washington, DC.

Summary: Parkinson´s disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic neurons in the substantia nigra compacta (SNpc). Non-motor symptoms such as neuropsychiatric, sleep and breathing disorders are also observed in PD. Previous study has already demonstrated that in 6-hydroxydopamine (6-OHDA)-model of PD there is a reduction in the number of phox2b neurons in the retrotrapezoid nucleus (RTN) and a decrease in the respiratory response to hypercapnia. Here, we tested the involvement of orexin cells from lateral hypothalamus/perifornical area (LH/PeF) on breathing in this model of PD. 6-OHDA (24 µg/µl) injections into the striatum reduced the number of catecholaminergic (40 days: 128 ± 10 and 60 days: 116 ± 13 vs. vehicle: 938 ± 15 neurons) and orexin-B-ir neurons (40 days: 310 ± 9 and 60 days: 258 ± 15 vs. vehicle: 412 ± 13 neurons). The injection of anti-Orexin-B saporin into the LH/PeF produces a further reduction in the number of orexinergic neurons in PD animals (79 ± 8 vs. control: 427 ± 14 neurons). The respiratory frequency (fR) at rest and in response to hypercapnia (7% CO2) was assessed 60 days after bilateral 6-OHDA or vehicle injections into the striatum and anti-Orexin-B saporin or IgG saporin into the LH/PeF during sleep and wakefulness in the dark and light phases of the diurnal cycle. Sixty days after 6-OHDA, we observed a reduction of fR at rest during sleep in the light phase only in PD animals (56 ± 2 vs. control: 66 ± 2 bpm). During the dark phase, there is a reduction in fR response to hypercapnia in PD animals with depletion of orexinergic neurons during wakefulness (119 ± 6 vs. control: 152 ± 3 bpm) and sleep (128 ± 7 vs. control: 147 ± 5 bpm). Our data suggest that orexinergic neurons are important to restore chemoreceptor function in a rat model of PD during sleep and wakefulness in rats.

Related Products: Orexin-B-SAP (Cat. #IT-20)

ATS Poster of the Year Winner

Kucinski AJ, De Jong IEM, Sarter M (2016) Preventing falls in PD in a rat model of impaired cognitive control of complex movements by a pro-cholinergic combination treatment. Neuroscience 2016 Abstracts 835.15 / III34. Society for Neuroscience, San Diego, CA.

Summary: Parkinson’s disease (PD) patients, in addition to primary motor symptoms resulting from extensive losses of striatal dopamine (DA), suffer from an interrelated group of motor-control symptoms including postural instability, gait deficits, and a propensity for falls. These levodopa-insensitive symptoms are associated with losses of cortically-projecting cholinergic neurons of the basal forebrain (BF), as well as cognitive impairments such as poor attention. Given the high prevalence and severe consequences of falls in levodopa-treated patients, alternative treatment options are urgently needed. To assess potential treatments we have developed behavioral models of falls in rats including a test system (Michigan Complex Motor Control Task, MCMCT) that requires persistent control of gait, limb coordination, and carefully timed and placed steps during traversals of dynamic surfaces (rotating square rods). Rats with bilateral cholinergic lesions of the BF using 192 IgG-saporin and 6-OHDA lesions to the dopaminergic dorsomedial striatum (dual lesions, DL) exhibit falls while traversing rotating rods and these falls correlate with impaired performance of a sustained attention task. DL rats’ falls have been hypothesized to result from interactions between disruption of normally cholinergically-driven transfer of extero- and interoceptive cue information from cortex to striatum and impaired striatal action sequencing. Here we tested the hypothesis that falls are reduced by co-treatment with acetylcholinesterase inhibitor donepezil and a 5-HT6 receptor antagonist. This combination treatment was previously reported to exhibit synergistic pro-cholinergic activity in rats and improved cognition in patients with moderate Alzheimer’s disease. Overall, drug-treated rats fell less frequently from the rotating rods and were particularly more efficient at reinstating forward movement after sudden stoppages of forward movement with a passive (doorframe) distractor task. This treatment combination may benefit fall propensity in PD patients via maintaining planned movement sequences in working memory and improving the vigor of executing such movements following brief periods of freezing of gait. The neuropharmacological interactions of this treatment may involve diverse signaling pathways converging onto striatal output neurons. Results from current experiments using microdialysis and HPLC-mass spectrometry to simultaneously assess release of striatal ACh, animo acids and monoamines during rotating rod traversals will assist in elucidating potential targets for therapeutic prevention of falls. Supported by a grant from H. Lundbeck A/S

Related Products: 192-IgG-SAP (Cat. #IT-01)

Kucinski A, de Jong IEM, Sarter M (2017) Reducing falls in Parkinson’s disease: interactions between donepezil and the 5‐HT6 receptor antagonist idalopirdine on falls in a rat model of impaired cognitive control of complex movements. Eur J Neurosci 45:217-231.. doi: 10.1111/ejn.13354

Objective: To assess the effects of treatment on MCMCT performance and attention in DL rats. The combined treatment of the acetylcholinesterase inhibitor donepezil and the 5-HT6 receptor antagonist idalopirdine (Lu AE58054) was use because it has been reported to exhibit synergistic pro-cholinergic activity in rats and improved cognition in patients with moderate Alzheimer’s disease.

Summary: This treatment may reduce fall propensity in patients.

Usage: 192-IgG-SAP aCSF infused bilaterally (120 ng/uL; 0.5 uL/hemisphere).

Related Products: 192-IgG-SAP (Cat. #IT-01)

Lee J, Jeong D, Lee J, Chang W, Chang J (2016) The effect of nucleus basalis magnocellularis deep brain stimulation on memory function in a rat model of dementia. BMC Neurol 16:6. doi: 10.1186/s12883-016-0529-z

Objective: Deep brain stimulation (DBS) is the application of electrical impulses to specific parts of the brain for treating disorders such as Parkinson’s disease, chronic pain, and obsessive-compulsive disorder. This study investigated whether stimulation of brain structures associated with memory can enhance cognitive function.

Summary: Results indicate that DBS has beneficial effects on consolidation and retrieval of visuospatial memory.

Usage: The authors lesioned the basal forebrain of rats through bilateral injections totaling 5 μg of 192-IgG-SAP into the lateral ventricle. Animals then received DBS to the nucleus basalis magnocellularis and were tested in a Morris water maze task.

Related Products: 192-IgG-SAP (Cat. #IT-01)

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)

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)

Read the featured article in Targeting Trends.

See Also:

• Phillips K et al. Impairments in gait, posture and complex movement control in rats modeling the multi-system, cholinergic-dopaminergic losses in PD. Neuroscience 2014 Abstracts 692.21, 2014. Society for Neuroscience, Washington, DC

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.