Deficit in sustained attention following selective cholinergic lesion of the pedunculopontine tegmental nucleus in rat, as measured with both post-mortem immunocytochemistry and in vivo PET imaging with [18F]fluoroethoxybenzovesamicol

Cyr, Marilyn; Parent, Maxime; Mechawar, Naguib; Rosa‐Neto, Pedro; Soucy, Jean‐Paul; Clark, Stewart D.; Aghourian, Meghmik; Bédard, Marc-André

doi:10.1016/j.bbr.2014.09.021

Cited by 32 publications

(33 citation statements)

References 55 publications

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“…It would be of interest to test this working hypothesis of the function of cholinergic PPTg by assessing the effects of loss of cholinergic Brain Struct Funct PPTg neurons in behavioral tasks with a considerably stronger reliance on multi-modal integration of information-for example, context-dependent instrumental learning (Corbit and Balleine 2000;Reichelt et al 2011), occasion setting (Reichelt et al 2011) or cue-driven behavioral changes, which are known to be highly susceptible to cholinergic manipulation (Palmatier et al 2006;Farquhar et al 2012). Consistent with this hypothesis, loss of cholinergic PPTg neurons reduces the number of correct responses and increases the variability in response latency during performance of the cue-driven 5-choice serial reaction time task (5-CSRTT) assessment of sustained attention (Cyr et al 2014).…”

Section: Relation To Previous Work: Nicotine Sensitizationmentioning

confidence: 70%

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

2015

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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.

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Section: Relation To Previous Work: Nicotine Sensitizationmentioning

confidence: 70%

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

2015

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“…PPTg forms functionally distinct innervations to the midbrain (Oakman et al, 1995, Watabe-Uchida et al, 2012, Wilson et al, 2009). Previous studies have shown that PPTg lesion results in attention deficit (Cyr et al, 2015, Inglis et al, 2001) as well as failure to develop conditioned responding to the reward-predictive cue (Inglis et al, 2000), suggesting that PPTg is involved in relaying sensory information for stimulus-reward associative learning. Here, our study has selectively targeted PPTg projections to the VTA and shown that acquisition of conditioned anticipatory responding in Pavlovian conditioning is differentially dependent on phenotypically distinct efferents from the PPTg.…”

Section: Discussionmentioning

confidence: 99%

Pontomesencephalic Tegmental Afferents to VTA Non-dopamine Neurons Are Necessary for Appetitive Pavlovian Learning

et al. 2016

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The ventral tegmental area (VTA) receives phenotypically distinct innervations from the pedunculopontine tegmental nucleus (PPTg). While PPTg-to-VTA inputs are thought to play a critical role in stimulus-reward learning, direct evidence linking PPTg-to-VTA phenotypically distinct inputs in the learning process remains lacking. Here, we used optogenetic approaches to investigate the functional contribution of PPTg excitatory and inhibitory inputs to the VTA in appetitive Pavlovian conditioning. We show that photoinhibition of PPTg-to-VTA cholinergic or glutamatergic inputs during cue presentation dampens the development of anticipatory approach responding to the food receptacle during the cue. Furthermore, we employed in vivo optetrode recordings to show that photoinhibition of PPTg cholinergic or glutamatergic inputs significantly decreases VTA non-dopamine (non-DA) neural activity. Consistently, photoinhibition of VTA non-DA neurons disrupts the development of cue-elicited anticipatory approach responding. Taken together, our study reveals a crucial regulatory mechanism by PPTg excitatory inputs onto VTA non-DA neurons during appetitive Pavlovian conditioning.

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“…Thus, at least at the level of the MRF, locomotion and waking state should not be considered independently but rather as two associated fundamental functions processed at least in part in the MRF. Interestingly, specific lesion of cholinergic neurons in rat was found to be associated with deficit in sustained attention in a proportional manner, suggesting that these neurons would have an active role in the neuronal network associated with the control of attentionnal process (Cyr et al 2015). By means of their strong projections onto intralaminar thalamic nuclei and BG (Paré et al 1988;Lavoie and Parent 1994a, b;Benarroch 2008;Martinez-Gonzalez et al 2011;Smith et al 2011) the MRF neurons could in fact be involved in the maintenance of the optimal level of attention to improve task performance Smith et al 2011;Okada and Kobayashi 2015) including locomotion.…”

Section: Mrf Neurons Involved In Wakingmentioning

confidence: 97%

The primate pedunculopontine nucleus region: towards a dual role in locomotion and waking state

et al. 2016

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The mesencephalic reticular formation (MRF) mainly composed by the pedunculopontine and the cuneiform nuclei is involved in the control of several fundamental brain functions such as locomotion, rapid eye movement sleep and waking state. On the one hand, the role of MRF neurons in locomotion has been investigated for decades in different animal models, including in behaving nonhuman primate (NHP) using extracellular recordings. On the other hand, MRF neurons involved in the control of waking state have been consistently shown to constitute the cholinergic component of the reticular ascending system. However, a dual control of the locomotion and waking state by the same groups of neurons in NHP has never been demonstrated in NHP. Here, using microelectrode recordings in behaving NHP, we recorded 38 neurons in the MRF that were followed during transition between wakefulness (TWS) and sleep, i.e., until the emergence of sleep episodes characterized by typical cortical slow wave activity (SWA). We found that the MRF neurons, mainly located in the pedunculopontine nucleus region, modulated their activity during TWS with a decrease in firing rate during SWA. Of interest, we could follow some MRF neurons from locomotion to SWA and found that they also modulated their firing rate during locomotion and TWS. These new findings confirm the role of MRF neurons in both functions. They suggest that the MRF is an integration center that potentially allows to fine tune waking state and locomotor signals in order to establish an efficient locomotion.

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Deficit in sustained attention following selective cholinergic lesion of the pedunculopontine tegmental nucleus in rat, as measured with both post-mortem immunocytochemistry and in vivo PET imaging with [18F]fluoroethoxybenzovesamicol

Cited by 32 publications

References 55 publications

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

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

Pontomesencephalic Tegmental Afferents to VTA Non-dopamine Neurons Are Necessary for Appetitive Pavlovian Learning

The primate pedunculopontine nucleus region: towards a dual role in locomotion and waking state

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