Selective lesions of the cholinergic neurons within the posterior pedunculopontine do not alter operant learning or nicotine sensitization

Abstract

Cholinergic neurons within the pedunculopontine tegmental nucleus have been implicated in a range of functions, including behavioral state control, attention, and modulation of midbrain and basal ganglia systems. Previous experiments with excitotoxic lesions have found persistent learning impairment and altered response to nicotine following lesion of the posterior component of the PPTg (pPPTg). These effects have been attributed to disrupted input to midbrain dopamine systems, particularly the ventral tegmental area. The pPPTg contains a dense collection of cholinergic neurons and also large numbers of glutamatergic and GABAergic neurons. Because these interdigitated populations of neurons are all susceptible to excitotoxins, the effects of such lesions cannot be attributed to one neuronal population. We wished to assess whether the learning impairments and altered responses to nicotine in excitotoxic PPTg-lesioned rats were due to loss of cholinergic neurons within the pPPTg. Selective depletion of cholinergic pPPTg neurons is achievable with the fusion toxin Dtx-UII, which targets UII receptors expressed only by cholinergic neurons in this region. Rats bearing bilateral lesions of cholinergic pPPTg neurons (>90% ChAT+ neuronal loss) displayed no deficits in the learning or performance of fixed and variable ratio schedules of reinforcement for pellet reward. Separate rats with the same lesions had a normal locomotor response to nicotine and furthermore sensitized to repeated administration of nicotine at the same rate as sham controls. Previously seen changes in these behaviors following excitotoxic pPPTg lesions cannot be attributed solely to loss of cholinergic neurons. These findings indicate that non-cholinergic neurons within the pPPTg are responsible for the learning deficits and altered responses to nicotine seen after excitotoxic lesions. The functions of cholinergic neurons may be related to behavioral state control and attention rather than learning.

Pedunculopontine tegmental nucleus lesions impair probabilistic reversal learning by reducing sensitivity to positive reward feedback

“…Thus, when rats had to switch response patterns to a condition in which outcomes were uncertain, posterior PPTg lesions impaired performance. The present study did not attempt to distinguish between the anterior and posterior PPTg, although neuronal loss primarily occurred in the posterior PPTg as defined in previous studies (Wilson et al 2009; MacLaren et al 2015a,b). Taken together, the findings from these studies suggest that the posterior PPTg facilitates a switch in response patterns under conditions in which outcomes are uncertain.…”

Participation of the pedunculopontine tegmental nucleus in arousal-demanding functions

“…For instance, rats with an ibotenate-induced loss of PPTg neurons or a selective loss of ACh neurons induced by diphtheria toxin conjugated to urotensin-II showed no deficits in learning or performance during fixed-or variable-ratio paradigms for reinforcement. The rats also had a normal locomotor response to nicotine, and they were not impaired in either cocaine or heroin self-administration or in the development of cocaine or heroin conditioned place preferences [136,147,148]. Yet, neither ibotenate-induced partial nor complete lesions of the PPTg caused locomotor deficits [149], as would be expected given the involvement of the PPTg in the mesencephalic locomotor region.…”

Dynamic changes in murine forebrain miR-211 expression associate with cholinergic imbalances and epileptiform activity

“…In the Morris water maze, dTg-211 mice presented delayed progression in search strategy and reduced reference memory abilities in probe trials. The impaired allocentric navigation phenotype may be attributed to impaired hippocampal, entorhinal cortex and some surrounding structures, the functioning of which is strongly modulated by the cholinergic system (51,52,72).…”

“…S6 C and D). Thus, dTg-211 mice presented a specific functional phenotype of impaired allocentric navigation, a disability attributed to functional impairments in the hippocampus, entorhinal cortex, and some surrounding structures, the functioning of which is strongly modulated by the cholinergic system (51,52).…”