The pedunculopontine tegmental nucleus and the nucleus basalis magnocellularis: do both have a role in sustained attention?

BACKGROUND: It 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. RESULTS: Both 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. CONCLUSION: The 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.

Involvement of the laterodorsal tegmental nucleus in the locomotor response to repeated nicotine administration.

The locomotor altering properties of nicotine depend on activation of nicotinic acetylcholine receptors in the ventral tegmental area (VTA). The laterodorsal tegmental nucleus (LDTg) provides a significant proportion of the cholinergic innervation of the VTA. We tested the hypothesis that the locomotor effects of nicotine depend on the functional integrity of the LDTg. The spontaneous locomotor activity of LDTg and sham-lesioned control rats was measured over seven sessions, after which we examined the effects of repeated injections of nicotine in a day on-day off design, giving injections of saline on the nicotine-off days. Spontaneous locomotor activity was significantly lower in LDTg lesioned compared to control rats. LDTg lesions also blunted the effects of nicotine: control rats showed an initial locomotor depression after nicotine, but on repeated testing showed a progressive increase in the amount of locomotion in response to drug challenge. LDTg lesioned rats showed no differences in responding to nicotine compared to saline. These data show that the functional integrity of the LDTg is required in order to show normal locomotor response to nicotine. One explanation for this is that loss of the LDTg affects synaptic activity in the VTA.

Impaired delayed spatial win-shift behaviour on the eight arm radial maze following excitotoxic lesions of the medial prefrontal cortex in the rat.

The delayed spatial win-shift (DSWS) radial maze task requires that animals hold spatial information for reward location "on-line" both during task performance and across a delay. Temporary lidocaine inactivation of anterior cingulate (AC) and prelimbic (PL) regions of the rat medial prefrontal cortex (mPFC) has revealed dissociable effects on this task, suggesting different roles within working memory for each of these areas. However, further research has shown that mPFC deficits in the rat may only be transient in nature, particularly on the radial maze. The present study was conducted to examine the effects of permanent excitotoxic lesions of the mPFC in the DSWS task across repeated trials to assess whether change in the degree of impairment would occur over time. Results showed that rats with lesions centred on the prelimbic cortex (but with damage extending into the anterior cingulate) were impaired on the post-delay test phase of the DSWS task. This deficit was characterised by increased errors (both across and within phase), earlier error occurrence, and increased latencies. Only the number of choices correct before error improved across repeated test days. These results are consistent with the involvement of the rat mPFC in spatial working memory and response inhibition, supporting previous findings using transient lesions. However, the discovery that rats with mPFC lesions learned to delay the intrusion of errors into their choice sequence extends previous work, and provides support for studies showing that mPFC lesioned rats can improve some aspects of task performance given the opportunity to learn over repeated trials.

Effects of changing reward on performance of the delayed spatial win-shift radial maze task in pedunculopontine tegmental nucleus lesioned rats.

Because it was designed to assess working memory, the delayed spatial win-shift (DSWS) radial maze task has been used to investigate the involvement of corticostriatal structures in executive processing. Excitotoxic lesions of the pedunculopontine tegmental nucleus (PPTg) produce profound deficits in performance of this task that are not accounted for by motor impairment. Thus, PPTg DSWS deficits are hypothesized to support a role for PPTg in complex cognitive processing. However, other studies indicate that the behaviour of PPTg lesioned rats varies depending on level of motivational excitement, assessed by the presence or absence of deprivation, or by manipulations of reward value. Since DSWS performance may also be affected by motivational dysfunction, the present experiment was conducted to examine the effects of post-surgical presentation of a more positive food reward (chocolate drops) on the DSWS retention performance of PPTg lesioned rats. Results confirmed a PPTg lesion deficit: lesioned rats made significantly more errors in both training and test phases, and made errors significantly earlier in their choice sequence in the test phase. Main effects of phase on number of errors indicated that the PPTg test phase deficit was not simply the result of a carry-over impairment from the training phase. PPTg rats receiving chocolate made significantly fewer errors than PPTg rats receiving food pellets. Results suggest that PPTg DSWS deficits are not the result of altered motivation or hedonic appreciation of reward value (or reward change) and therefore support the hypothesis of executive cognitive deficits in PPTg lesioned rats.

Determination of acetylcholine and dopamine content in thalamus and striatum after excitotoxic lesions of the pedunculopontine tegmental nucleus in rats.

The pedunculopontine tegmental nucleus (PPTg) contains cholinergic neurons whose principal ascending connections are with thalamic nuclei and structures associated with the striatum. It has been hypothesized that PPTg neurons are more closely associated with the substantia nigra (and therefore striatal motor systems) than with the ventral tegmental area (and therefore limbic striatal functions). In the present experiments we have examined the hypothesis that the PPTg is similarly associated with motor nuclei in the thalamus. Rats received unilateral ibotenate lesions of PPTg and were sacrificed 1, 2, 4 or 7 days later. Discrete thalamic nuclei, and samples of caudate-putamen and nucleus accumbens, were punched out and thalamic acetylcholine (ACh) and striatal ACh and dopamine (DA) content examined. Anteroventral nucleus had decreased ACh content after PPTg lesion, but a time dependent increase was found in mediodorsal nucleus; ACh concentration was unchanged in thalamic reticular nucleus or medial geniculate. No long-term lesion-dependent changes in striatal ACh or DA content were found. The effects of PPTg lesion on thalamic ACh content are consistent with the hypothesis that it has effects on motor nuclei, but also indicate that PPTg lesions have complex and dynamic effects on thalamic ACh content.

Nicotine self-administered directly into the VTA by rats is weakly reinforcing but has strong reinforcement enhancing properties.

RATIONALE: Rats will lever press to deliver nanolitre quantities of nicotine or the muscarinic agonist carbachol directly into the ventral tegmental area (VTA). The purpose of these experiments was to investigate further the characteristics of nicotine self-administration directly into the VTA. OBJECTIVES: This study aimed to confirm previous data relating to intra-VTA self-administration of nicotine and carbachol and then test two hypotheses: (a) that pre-sensitisation of nicotinic receptors is needed for robust intra-VTA self administration and (b) that rats will lever press for intra-VTA nicotine if pre-trained to associate lever pressing with a rewarding outcome. METHODS: Rats were equipped with cannulae aimed at posterior VTA and allowed five sessions to self-administer nicotine or carbachol. In different experiments, rats were either pre-sensitised to nicotine by subcutaneous (s.c.) injections or pre-trained to lever press for food and a simultaneous conditioned stimulus light. RESULTS: We confirmed that carbachol had strong activating effects when self-administered into the VTA; selective responding for nicotine developed over five sessions by reduction in the amount of pressing on an inactive lever. Prior sensitisation did not improve responding for intra-VTA nicotine but training rats to lever press before putting them on the drug regime did potentiate pressing. CONCLUSIONS: The action of nicotine in the VTA might be better considered as reinforcement enhancing and that its intrinsic rewarding property here is at best weak. Identification of the VTA as a target for the reinforcement enhancing effects of nicotine is compatible with the reinforcement-related functions of VTA dopamine neurons and their cholinergic inputs.

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

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.

Intravenous self-administration of nicotine is altered by lesions of the posterior, but not anterior, pedunculopontine tegmental nucleus.

The reinforcing properties of nicotine involve actions at nicotinic acetylcholine receptors located on dopamine (DA) neurons in the ventral tegmental area (VTA). The pedunculopontine tegmental nucleus (PPTg) is involved in the regulation of these DA neurons, and those of the substantia nigra pars compacta (SNc). The PPTg can be subdivided into anterior (aPPTg) and posterior (pPPTg) regions on the basis of its innervation of midbrain DA neurons - the pPPTg innervates both VTA and SNc while the aPPTg innervates SNc. As the reinforcing actions of nicotine depend on its actions in the VTA more than SNc, it was hypothesized that excitotoxic lesions of pPPTg would alter nicotine reinforcement, measured by intravenous self-administration, while lesions of aPPTg would not. Rats were given ibotenate lesions of pPPTg or aPPTg, followed by intravenous catheterization. Intravenous self-administration (IVSA) of nicotine (0.03 mg/kg/inf) was carried out until a stable response baseline was reached. A dose-response function for nicotine was then established. There was no significant effect of aPPTg lesions on nicotine IVSA, while IVSA was significantly elevated following pPPTg lesions, compared with both sham lesioned controls and aPPTg excitotoxin lesioned rats. This was found across all doses, including saline, of the dose-response function. The differential effect of aPPTg lesions and pPPTg lesions suggests that disruption of regulatory innervation from pPPTg results in altered regulation of VTA DA neurons. The resulting change in nicotine self-administration behaviour was hypothesized to reflect either a reduction in intrinsic nicotine reward value, or enhancement of associative incentive salience.

The pedunculopontine tegmental nucleus and responding for sucrose reward.

Pedunculopontine tegmental nucleus (PPTg) lesions in rodents lead to increased sucrose consumption, but the psychological deficit behind this remains uncertain. To understand better the relationship between consumption of, and motivation for, sucrose, the authors trained rats to traverse a runway for 20% or 4% sucrose solution; after 7 days, concentrations were reversed. Control rats consumed more 20% than 4% sucrose solution and promptly altered run times in response to concentration change. PPTg-lesioned rats consumed normal quantities of 4% but more 20% sucrose solution than controls and took longer to alter their runway time following the concentration change. These data suggest that lesions of the PPTg do not alter motivation per se and might be better understood as inducing a response selection deficit.

Excitotoxic lesions of the pedunculopontine tegmental nucleus in rats impair performance on a test of sustained attention.

Recent research has suggested that the pontomesencephalic tegmentum might be an important part of a network underlying sustained attention. The largest structure of the pontomesencephalic tegmentum is the pedunculopontine tegmental nucleus, which has ascending connections to thalamus and with corticostriatal systems. In this experiment we examined the performance of rats following bilateral excitotoxic lesions of the pedunculopontine tegmental nucleus on a test of sustained attention previously used to examine frontal cortical function. After an initial period of darkness, the rats had to attend continuously to a dim stimulus light that would, at unpredictable intervals, become transiently brighter. During this period of increased stimulus brightness the rats could press a lever to obtain a food reward. Rats were trained to a criterion level of performance before lesions were made. After surgery, sham lesioned rats (n=7) resumed accurate responding, with an average successful detection rate of approximately 70%. Pedunculopontine lesioned rats (n=7), however, only achieved a successful detection rate of approximately 40%. When the duration of the bright target stimulus was increased from 1.5 to 4 s, the performance of the pedunculopontine lesioned rats significantly improved. The observation that an increase in brightness duration caused a marked improvement in lesioned rats' performance suggests strongly that the impairment was in attention rather than motor ability or simple sensory processing. These data are taken to be consistent with the hypothesis that the pedunculopontine tegmental nucleus is an important part of a network maintaining attention.