Deep brain stimulation of different pedunculopontine targets in a novel rodent model of parkinsonism.

The pedunculopontine tegmental nucleus (PPTg) has been proposed as a target for deep brain stimulation (DBS) in parkinsonian patients, particularly for symptoms such as gait and postural difficulties refractory to dopaminergic treatments. Several patients have had electrodes implanted aimed at the PPTg, but outcomes have been disappointing, with little evidence that gait and posture are improved. The PPTg is a heterogeneous structure. Consequently, exact target sites in PPTg, possible DBS mechanisms, and potential benefits still need systematic investigation in good animal models. We have investigated the role of PPTg in gait, developed a refined model of parkinsonism including partial loss of the PPTg with bilateral destruction of nigrostriatal dopamine neurons that mimics human pathophysiology, and investigated the effect of DBS at different PPTg locations on gait and posture using a wireless device that lets rats move freely while receiving stimulation. Neither partial nor complete lesions of PPTg caused gait deficits, underlining questions raised previously about the status of PPTg as a motor control structure. The effect of DBS in the refined and standard model of parkinsonism were very different despite minimal behavioral differences in nonstimulation control conditions. Anterior PPTg DBS caused severe episodes of freezing and worsened gait, whereas specific gait parameters were mildly improved by stimulation of posterior PPTg. These results emphasize the critical importance of intra-PPTg DBS location and highlight the need to take PPTg degeneration into consideration when modeling parkinsonian symptoms. They also further implicate a role for PPTg in the pathophysiology of parkinsonism.

The pedunculopontine tegmental nucleus-A functional hypothesis from the comparative literature.

We present data from animal studies showing that the pedunculopontine tegmental nucleus-conserved through evolution, compartmentalized, and with a complex pattern of inputs and outputs-has functions that involve formation and updates of action-outcome associations, attention, and rapid decision making. This is in contrast to previous hypotheses about pedunculopontine function, which has served as a basis for clinical interest in the pedunculopontine in movement disorders. Current animal literature points to it being neither a specifically motor structure nor a master switch for sleep regulation. The pedunculopontine is connected to basal ganglia circuitry but also has primary sensory input across modalities and descending connections to pontomedullary, cerebellar, and spinal motor and autonomic control systems. Functional and anatomical studies in animals suggest strongly that, in addition to the pedunculopontine being an input and output station for the basal ganglia and key regulator of thalamic (and consequently cortical) activity, an additional major function is participation in the generation of actions on the basis of a first-pass analysis of incoming sensory data. Such a function-rapid decision making-has very high adaptive value for any vertebrate. We argue that in developing clinical strategies for treating basal ganglia disorders, it is necessary to take an account of the normal functions of the pedunculopontine. We believe that it is possible to use our hypothesis to explain why pedunculopontine deep brain stimulation used clinically has had variable outcomes in the treatment of parkinsonism motor symptoms and effects on cognitive processing. © 2016 International Parkinson and Movement Disorder Society.

The roles of the nucleus accumbens core, dorsomedial striatum, and dorsolateral striatum in learning: performance and extinction of Pavlovian fear-conditioned responses and instrumental avoidance responses.

This study examined the effects of bilateral excitotoxic lesions of the nucleus accumbens core (NAc-co), dorsomedial striatum (DMS) or dorsolateral striatum (DLS) of rats on the learning and extinction of Pavlovian and instrumental components of conditioned avoidance responses (CARs). None of the lesions caused sensorimotor deficits that could affect locomotion. Lesions of the NAc-co, but not DMS or DLS, decreased unconditioned and conditioned freezing. The NAc-co and DLS lesioned rats learned the 2-way active avoidance task more slowly. These results suggest: (i) CARs depend on both Pavlovian and instrumental learning; (ii) learning the Pavlovian component of CARs depends on the NAc-co; learning the instrumental component of CARs depends on the DLS, NAc and DMS; (iii) although the NAc-co is also needed for learning the instrumental component, it is not clear whether it plays a role in learning the instrumental component per se or if it simply allows learning of the Pavlovian component which is a pre-condition for learning the instrumental component; (iv) we did not find evidence that the DMS and DLS play the same roles in habit and goal-directed aspects of the instrumental component of CARs as observed in appetitive motivated instrumental responding.

Updating of action-outcome associations is prevented by inactivation of the posterior pedunculopontine tegmental nucleus.

The pedunculopontine tegmental nucleus (PPTg) is in a pivotal position between the basal ganglia and brainstem: it is able to influence and regulate all levels of basal ganglia and corticostriatal activity as well as being a key component of brainstem reticular and motor control circuitry. Consistent with its anatomical position, the PPTg has previously been shown to process rapid, salient sensory input, is a target for Parkinson's disease treatments and has been implicated in associative learning. We explicitly investigated the role of the posterior pPPTg (pPPTg) in action-outcome processes, where actions are performed with the goal-directed aim of obtaining an anticipated outcome. We assessed rats' sensitivity to degradation of the contingency between actions (lever pressing) and outcomes (food reward) during either inactivation of pPPTg by microinjection of the GABA agonist muscimol or control infusions of saline. In response to the degradation of contingency between lever press and food reward, saline treated rats rapidly reduced rates of lever pressing whereas muscimol treated rats (pPPTg inactivation) maintained previous lever pressing rates. In contrast, when the contingency between lever press and food reward was unchanged saline and muscimol treated rats maintained their previous rates of lever pressing. This shows that the pPPTg is critically required for updating associations between actions and outcomes, but not in the continued performance of previously learned associations. These results are consistent with a role for the PPTg in 'higher-order' associative learning and are the first to demonstrate a brainstem role in action-outcome learning.

The role of nucleus accumbens and dorsolateral striatal D2 receptors in active avoidance conditioning.

The role of dopamine (DA) in rewarding motivated actions is well established but its role in learning how to avoid aversive events is still controversial. Here we tested the role of D2-like DA receptors in the nucleus accumbens (NAc) and the dorsolateral striatum (DLS) of rats in the learning and performance of conditioned avoidance responses (CAR). Adult male Wistar rats received systemic, intra-NAc or intra-DLS (pre- or post-training) administration of a D2-like receptor agonist (quinpirole) or antagonist ((-)sulpiride) and were given two sessions in the two-way active avoidance task. The main effects observed were: (i) sulpiride and lower (likely pre-synaptic) doses of quinpirole decreased the number of CARs and increased the number of escape failures; (ii) higher doses of quinpirole (likely post-synaptic) increased inter-trial crossings and failures; (iii) pre-training administration of sulpiride decreased the number of CARs in both training and test sessions when infused into the NAc, but this effect was observed only in the test session when it was infused into the DLS; (iv) post-training administration of sulpiride decreased CARs in the test session when infused into the NAc but not DLS. These findings suggest that activation of D2 receptors in the NAc is critical for fast adaptation to responding to unconditioned and conditioned aversive stimuli while activation of these receptors in the DLS is needed for a slower learning of how to respond to the same stimuli based on previous experiences.

Functional disconnection of the substantia nigra pars compacta from the pedunculopontine nucleus impairs learning of a conditioned avoidance task.

The pedunculopontine tegmental nucleus (PPTg) targets nuclei in the basal ganglia, including the substantia nigra pars compacta (SNc), in which neuronal loss occurs in Parkinson's disease, a condition in which patients show cognitive as well as motor disturbances. Partial loss and functional abnormalities of neurons in the PPTg are also associated with Parkinson's disease. We hypothesized that the interaction of PPTg and SNc might be important for cognitive impairments and so investigated whether disrupting the connections between the PPTg and SNc impaired learning of a conditioned avoidance response (CAR) by male Wistar rats. The following groups were tested: PPTg unilateral; SNc unilateral; PPTg-SNc ipsilateral (ipsilateral lesions in PPTg and SNc); PPTg-SNc contralateral (contralateral lesions in PPTg and SNc); sham lesions (of each type). SNc lesions were made with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine HCl (MPTP, 0.6micromol); PPTg lesions with ibotenate (24nmol). After recovery, all rats underwent 50-trial sessions of 2-way active avoidance conditioning for 3 consecutive days. Rats with unilateral lesions in PPTg or SNc learnt this, however rats with contralateral (but not ipsilateral) combined lesions in both structures presented no sign of learning. This effect was not likely to be due to sensorimotor impairment because lesions did not affect reaction time to the tone or footshock during conditioning. However, an increased number of non-responses were observed in the rats with contralateral lesions. The results support the hypothesis that a functional interaction between PPTg and SNc is needed for CAR learning and performance.

Bar pressing for food: differential consequences of lesions to the anterior versus posterior pedunculopontine.

The pedunculopontine tegmental nucleus (PPTg) is in a key position to participate in operant reinforcement via its connections with the corticostriatal architecture and the medial reticular formation. Indeed, previous work has demonstrated that rats bearing lesions of the whole PPTg are impaired when learning to make two bar presses for amphetamine reinforcement. Anterior and posterior portions of the PPTg make different anatomical connections, including preferential projections by the anterior PPTg to substantia nigra pars compacta dopamine neurons and by the posterior PPTg to ventral tegmental area dopamine neurons. We wanted to assess the effects of anterior and posterior PPTg ibotenate lesions on rats learning simple and more complex schedules of natural reinforcement. We trained rats with lesions to the anterior PPTg (n = 11) and the posterior PPTg (n = 5) [and appropriate controls (n = 15)] to bar press for food on a variety of fixed-ratio and variable-ratio reinforcement schedules and then during extinction. We found that posterior PPTg-lesioned rats bar pressed at lower rates, were slower to learn to bar press, and often had deficits characteristic of impaired learning and/or motivation. In contrast, anterior PPTg-lesioned rats learned to bar press for reinforcement at normal rates. However, they made errors of perseveration and anticipation throughout many schedules, and pressed at a higher rate than controls during extinction, deficits best characterized as reflecting disorganized response control. Together, these data suggest that the anterior PPTg and posterior PPTg (and their related circuits) contribute differently to reinforcement learning, incentive motivation, and response control, processes that are considered to malfunction in drug addiction.

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.

Experimental studies of pedunculopontine functions: are they motor, sensory or integrative?

The pedunculopontine tegmental nucleus (PPTg) is involved in Parkinson's disease and has become a therapeutic target. However, its normal functions are uncertain: are they motor, sensory or integrative? This position paper reviews PPTg structure and considers experiments designed to understand its behavioural functions. The PPTg is part of the corticostriatal architecture and, consistent with this, a core deficit following lesion is the inability to properly establish action-outcome associations. Understanding normal PPTg structure and function will provide insight into the role it has in Parkinson's disease and related disorders, and will benefit the development of surgical treatments aimed here.

The Cellular Diversity of the Pedunculopontine Nucleus: Relevance to Behavior in Health and Aspects of Parkinson's Disease.

The pedunculopontine nucleus (PPN) is a rostral brainstem structure that has extensive connections with basal ganglia nuclei and the thalamus. Through these the PPN contributes to neural circuits that effect cortical and hippocampal activity. The PPN also has descending connections to nuclei of the pontine and medullary reticular formations, deep cerebellar nuclei, and the spinal cord. Interest in the PPN has increased dramatically since it was first suggested to be a novel target for treating patients with Parkinson's disease who are refractory to medication. However, application of frequency-specific electrical stimulation of the PPN has produced inconsistent results. A central reason for this is that the PPN is not a heterogeneous structure. In this article, we review current knowledge of the neurochemical identity and topographical distribution of neurons within the PPN of both humans and experimental animals, focusing on studies that used neuronally selective targeting strategies to ascertain how the neurochemical heterogeneity of the PPN relates to its diverse functions in relation to movement and cognitive processes. If the therapeutic potential of the PPN is to be realized, it is critical to understand the complex structure-function relationships that exist here.

How best to consider the structure and function of the pedunculopontine tegmental nucleus: evidence from animal studies.

This review presents the hypothesis that the best way to consider the pedunculopontine tegmental nucleus is by analogy with the substantia nigra. The substantia nigra contains two main compartments: the pars compacta and the pars reticulata. The former contains dopamine neurons that project widely within the basal ganglia while the latter is in receipt of corticostriatal output. Similarly, the PPTg contains the Ch5 acetylcholine containing neurons that project to the thalamus and corticostriatal systems (notably the pars compacta of substantia nigra and the subthalamic nucleus) while the non-cholinergic neurons of the pedunculopontine are in receipt of corticostriatal output. Assessment of the location, composition and connections of the pedunculopontine tegmental nucleus is made to support the hypothesis that it has structural similarities with substantia nigra. Assessment of the motor, sensory and cognitive functions of the pedunculopontine is also made, suggesting functional similarities exist also. Having a clear model of pedunculopontine structure and function is a matter of some importance. It is clearly involved in Parkinson's disease and could potentially be a target for therapeutic intervention. If this is to be realized it will be best to have as clear an understanding as possible of pedunculopontine structure and function in order to maximize positive benefits.

Description and Evaluation of an MPharm Practice-based Experience Pilot Program.

Objective. To determine the level of support among pharmacists in central Scotland to serve as mentors and provide practice-based experience to students enrolled in a master of pharmacy degree program. Methods. A study was conducted during the 2011-2012 academic year in which first-year MPharm students in Scotland were paired with practicing pharmacists for 2 half-day visits per month. The students were integrated into the pharmacy workflow and engaged in activities ranging from date checking to counseling patients. The pharmacists and students who participated were asked to complete a survey in spring 2012 regarding their experiences and, in addition, the students were asked to maintain diary entries describing their experiences. Results. Thirty-nine students were paired successfully with 38 pharmacists. Every pharmacist stated their student was welcome to return in the 2012-2013 academic year and 29 agreed to accept a second student. Nine of 12 participating chain community pharmacies asked for program expansion and 11 chain community pharmacies and one other community pharmacy that did not participate in 2011-2012 asked to join in 2012-2013. Conclusion. Large numbers of pharmacists in central Scotland are willing to mentor and provide practice-based pharmacy education for students in a manner consistent with General Pharmaceutical Council accreditation standards for the master of pharmacy degree curriculum.

Qualitative Evaluation of a Practice-based Experience Pilot Program for Master of Pharmacy Students in Scotland.

Objective. To determine the views of pharmacists in central Scotland regarding experiential education for MPharm students. Methods. A thematic analysis was completed by Ms. Gillian Hendry and Dr. Sally Wiggins of interviews conducted with ten practicing pharmacists paired with first-year master of pharmacy (MPharm) students during the 2011-2012 academic year. Relevant comments from the interviews were manually sorted in a Microsoft Excel spreadsheet to bring similarly themed material together to facilitate the identification and naming of recurring themes and subthemes. Results. The pharmacists were unanimous in their opinion that experiential education was valuable for MPharm students and, in particular, that it helped students to develop self-confidence. The pharmacists derived personal satisfaction in developing mentor/mentee relationships with students. They also recognized the value that students provided to the workforce as well as the educational value to themselves in supervising students. The participants' primary dissatisfaction was that the pharmacy workflow limited the time they could spend mentoring students. Conclusion. The results provide guidance to the academic community and the pharmacy practice community in the United Kingdom (UK) regarding the design and integration of experiential education courses in MPharm degree programs.

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

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.

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.

An examination of the effects of bilateral excitotoxic lesions of the pedunculopontine tegmental nucleus on responding to sucrose reward.

The effects of bilateral excitotoxic lesions of the pedunculopontine tegmental nucleus (PPTg) on sucrose intake were examined in three experiments. First, in tests of conditioned place preference using 20% sucrose as the reinforcer, it was shown that lesioned rats, regardless of whether they were food deprived or non-deprived, formed normal place preferences and showed normal amounts of locomotion. However, consumption of 20% sucrose in the pairing trials was increased in the deprived PPTg lesioned rats compared to their matched controls. A second experiment showed that sucrose consumption in the home cage was increased in both deprived and non-deprived PPTg lesioned rats, but only when the concentration of sucrose was greater than 12%: below this there were no differences in intake between the lesioned and control rats. In a third home cage experiment, it was again shown that non-deprived PPTg lesioned rats increased their consumption of 20% sucrose compared to controls. PPTg lesioned rats concomitantly reduced their intake of lab chow such that overall energy intake remained the same as that of control rats. These data are taken to suggest (i) that bilateral excitotoxic lesions of the PPTg increase consumption of sucrose selectively in conditions of high motivational excitement; (ii) that the perception of the rewarding value of 20% sucrose, as judged by place preference, is not affected by these lesions; and (iii) that PPTg lesioned rats are able to adjust their energy intake to accommodate increased sucrose loads. These data are consistent with the hypothesis that bilateral excitotoxic lesions of the PPTg do not affect energy balance regulation or judgment of the hedonic value of sucrose, but that they do affect the control of responding in the face of high levels of motivational excitement.

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.

Evidence that conditioned avoidance responses are reinforced by positive prediction errors signaled by tonic striatal dopamine.

We conducted an experiment in which hedonia, salience and prediction error hypotheses predicted different patterns of dopamine (DA) release in the striatum during learning of conditioned avoidance responses (CARs). The data strongly favor the latter hypothesis. It predicts that during learning of the 2-way active avoidance CAR task, positive prediction errors generated when rats do not receive an anticipated footshock (which is better than expected) cause DA release that reinforces the instrumental avoidance action. In vivo microdialysis in the rat striatum showed that extracellular DA concentration increased during early CAR learning and decreased throughout training returning to baseline once the response was well learned. In addition, avoidance learning was proportional to the degree of DA release. Critically, exposure of rats to the same stimuli but in an unpredictable, unavoidable, and inescapable manner, did not produce alterations from baseline DA levels as predicted by the prediction error but not hedonic or salience hypotheses. In addition, rats with a partial lesion of substantia nigra DA neurons, which did not show increased DA levels during learning, failed to learn this task. These data represent clear and unambiguous evidence that it was the factor positive prediction error, and not hedonia or salience, which caused increase in the tonic level of striatal DA and which reinforced learning of the instrumental avoidance response.