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A functional dissociation of the anterior and posterior pedunculopontine tegmental nucleus: excitotoxic lesions have differential effects on locomotion and the response to nicotine.

ABSTRACT: Excitotoxic lesions of posterior, but not anterior pedunculopontine tegmental nucleus (PPTg) change nicotine self-administration, consistent with the belief that the anterior PPTg (aPPTg) projects to substantia nigra pars compacta (SNC) and posterior PPTg (pPPTg) to the ventral tegmental area (VTA). The VTA is a likely site both of nicotine's reinforcing effect as well as its actions on locomotion. We hypothesized that pPPTg, but not aPPTg lesions, would alter locomotion in response to repeated nicotine administration by virtue of the fact that pPPTg appears to be more closely related to the VTA than is the aPPTg. Following excitotoxic lesions of aPPTg or pPPTg, rats were habituated to experimental procedures. Repeated (seven of each) nicotine (0.4 mg/kg) and saline injections were given following an on-off procedure. Measurement of spontaneous locomotion during habituation showed that aPPTg but not pPPTg lesioned rats were hypoactive relative to controls. Following nicotine, control rats showed locomotor depression for the first 2 days of treatment followed by enhanced locomotion relative to activity following saline treatment. Rats with aPPTg lesions showed a similar pattern, but the pPPTg lesioned rats showed no locomotor depression following nicotine treatment. These data confirm the role of the pPPTg in nicotine's behavioural effects--including the development of sensitization--and demonstrate for the first time that excitotoxic lesions of the aPPTg but not pPPTg generate a deficit in baseline activity. The finding that anterior but not posterior PPTg affects motor activity has significance for developing therapeutic strategies for Parkinsonism using deep brain stimulation aimed here.

SUBMITTER: Alderson HL

PROVIDER: S-EPMC2522332 | biostudies-other | 2008 Sep

REPOSITORIES: biostudies-other

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Project description:Rats with lesions of the pedunculopontine tegmental nucleus (PPTg) reliably overconsume high concentration sucrose solution. This effect is thought to be indicative of response-perseveration or loss of behavioral control in conditions of high excitement. While these theories have anatomical and behavioral support, they have never been explicitly tested. Here, we used a contact lickometer to examine the microstructure of drinking behavior to gain insight into the behavioral changes during overconsumption. Rats received either excitotoxic (ibotenic acid) damage to all PPTg neuronal subpopulations or selective depletion of the cholinergic neuronal sub-population (diphtheria toxin-urotensin II (Dtx-UII) lesions). We offered rats a variety of pleasant, neutral and aversive tastants to assess the generalizability and specificity of the overconsumption effect. Ibotenic-lesioned rats consumed significantly more 20% sucrose than sham controls, and did so through licking significantly more times. However, the behavioral microstructure during overconsumption was unaffected by the lesion and showed no indications of response-perseveration. Furthermore, the overconsumption effect did not generalize to highly consumed saccharin. In contrast, while only consuming small amounts of quinine solution, ibotenic-lesioned rats had significantly more licks and bursts for this tastant. Selective depletion of cholinergic PPTg neurons had no effect on consumption of any tastant. We then assessed whether it is the salience of the solution which determines overconsumption by ibotenic-lesioned rats. While maintained on free-food, ibotenic-lesioned rats had normal consumption of sucrose and hypertonic saline. After mild food deprivation ibotenic PPTg-lesioned rats overconsumed 20% sucrose. Subsequently, after dietary-induced sodium deficiency, lesioned rats consumed significantly more saline than controls. These results establish that it is the salience of the solution which is the determining factor leading to overconsumption following excitotoxic PPTg lesion. They also find no support for response-perseveration contributing to this effect. Results are discussed in terms of altered dopamine (DA) and salience signaling.

Project description:BackgroundIt is well established that nucleus basalis magnocellularis (NbM) lesions impair performance on tests of sustained attention. Previous work from this laboratory has also demonstrated that pedunculopontine tegmental nucleus (PPTg) lesioned rats make more omissions on a test of sustained attention, suggesting that it might also play a role in mediating this function. However, the results of the PPTg study were open to alternative interpretation. We aimed to resolve this by conducting a detailed analysis of the effects of damage to each brain region in the same sustained attention task used in our previous work. Rats were trained in the task before surgery and post-surgical testing examined performance in response to unpredictable light signals of 1500 ms and 4000 ms duration. Data for PPTg lesioned rats were compared to control rats, and rats with 192 IgG saporin infusions centred on the NbM. In addition to operant data, video data of rats' performance during the task were also analysed.ResultsBoth lesion groups omitted trials relative to controls but the effect was milder and transient in NbM rats. The number of omitted trials decreased in all groups when tested using the 4000 ms signal compared to the 1500 ms signal. This confirmed previous findings for PPTg lesioned rats. Detailed analysis revealed that the increase in omissions in PPTg rats was not a consequence of motor impairment. The video data (taken on selected days) showed reduced lever orientation in PPTg lesioned rats, coupled with an increase in unconditioned behaviours such as rearing and sniffing. In contrast NbM rats showed evidence of inadequate lever pressing.ConclusionThe question addressed here is whether the PPTg and NbM both have a role in sustained attention. Rats bearing lesions of either structure showed deficits in the test used. However, we conclude that the most parsimonious explanation for the deficit observed in PPTg rats is inadequate response organization, rather than impairment in sustained attention. Furthermore the impairment observed in NbM lesioned rats included lever pressing difficulties in addition to impaired sustained attention. Unfortunately we could not link these deficits directly to cholinergic neuronal loss.

Project description:BackgroundThe etiology of cervical dystonia is unknown. Cholinergic abnormalities have been identified in dystonia animal models and human imaging studies. Some animal models have cholinergic neuronal loss in the striatum and increased acetylcholinesterase activity in the pedunculopontine nucleus.ObjectivesThe objective of this study was to determine the presence of cholinergic abnormalities in the putamen and pedunculopontine nucleus in cervical dystonia human brain donors.MethodsFormalin-fixed brain tissues were obtained from 8 cervical dystonia and 7 age-matched control brains (controls). Pedunculopontine nucleus was available in only 6 cervical dystonia and 5 controls. Neurodegeneration was evaluated pathologically in the putamen, pedunculopontine nucleus, and other regions. Cholinergic neurons were detected using choline acetyltransferase immunohistochemistry in the putamen and pedunculopontine nucleus. Putaminal cholinergic neurons were quantified. A total of 6 cervical dystonia patients and 6 age-matched healthy controls underwent diffusion tensor imaging to determine if there were white matter microstructural abnormalities around the pedunculopontine nucleus.ResultsDecreased or absent choline acetyltransferase staining was identified in all 6 pedunculopontine nucleus samples in cervical dystonia. In contrast, strong choline acetyltransferase staining was present in 4 of 5 pedunculopontine nucleus controls. There were no differences in pedunculopontine nucleus diffusion tensor imaging between cervical dystonia and healthy controls. There was no difference in numbers of putaminal cholinergic neurons between cervical dystonia and controls.ConclusionsOur findings suggest that pedunculopontine nucleus choline acetyltransferase deficiency represents a functional cholinergic deficit in cervical dystonia. Structural lesions and confounding neurodegenerative processes were excluded by absence of neuronal loss, gliosis, diffusion tensor imaging abnormalities, and beta-amyloid, tau, and alpha-synuclein pathologies. © 2018 International Parkinson and Movement Disorder Society.

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A functional dissociation of the anterior and posterior pedunculopontine tegmental nucleus: excitotoxic lesions have differential effects on locomotion and the response to nicotine.

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