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The loss of midbrain dopaminergic (DA) neurons is the fundamental pathological feature of Parkinson's disease (PD). PD causes chronic pain in two-thirds of patients. Recent studies showed that the activation of the pedunculopontine tegmental nucleus (PPTg) can effectively relieve inflammatory pain and neuropathic pain. The PPTg is located in the pontomesencephalic tegmentum, a target of deep brain stimulation (DBS) treatment in PD, and is involved in motor control and sensory integration. To test whether the lesion of midbrain DA neurons induced pain hypersensitivity, and whether the chemogenetic activation of the PPTg could modulate the pain, the AAV-hM3Dq receptor was transfected and expressed into the PPTg neurons of 6-hydroxydopamine-lesioned mice. In this study, von Frey, open field, and adhesive tape removal tests were used to assess animals' pain sensitivity, locomotor activity, and sensorimotor function and somatosensory perception, respectively. Here, we found that the lesion of midbrain DA neurons induced a minor deficit in voluntary movement but did not affect sensorimotor function and somatosensory perception in the tape removal test. The results showed that lesion led to pain hypersensitivity, which could be alleviated both by levodopa and by the chemogenetic activation of the PPTg. Activating the PPTg may be a potential therapeutic strategy to relieve pain phenotypes in PD. [ABSTRACT FROM AUTHOR]

The pedunculopontine nucleus (PPN) is a small brainstem structure and has attracted attention as a potentially effective deep brain stimulation (DBS) target for the treatment of Parkinson's disease (PD). However, the in vivo location of PPN remains poorly described and barely visible on conventional structural magnetic resonance (MR) images due to a lack of high spatial resolution and tissue contrast. This study aims to delineate the PPN on a high-resolution (HR) atlas and investigate the visibility of the PPN in individual quantitative susceptibility mapping (QSM) images. We combine a recently constructed Montreal Neurological Institute (MNI) space unbiased QSM atlas (MuSus-100), with an implicit representation-based self-supervised image super-resolution (SR) technique to achieve an atlas with improved spatial resolution. Then guided by a myelin staining histology human brain atlas, we localize and delineate PPN on the atlas with improved resolution. Furthermore, we examine the feasibility of directly identifying the approximate PPN location on the 3.0-T individual QSM MR images. The proposed SR network produces atlas images with four times the higher spatial resolution (from 1 to 0.25 mm isotropic) without a training dataset. The SR process also reduces artifacts and keeps superb image contrast for further delineating small deep brain nuclei, such as PPN. Using the myelin staining histological atlas as guidance, we first identify and annotate the location of PPN on the T1-weighted (T1w)-QSM hybrid MR atlas with improved resolution in the MNI space. Then, we relocate and validate that the optimal targeting site for PPN-DBS is at the middle-to-caudal part of PPN on our atlas. Furthermore, we confirm that the PPN region can be identified in a set of individual QSM images of 10 patients with PD and 10 healthy young adults. The contrast ratios of the PPN to its adjacent structure, namely the medial lemniscus, on images of different modalities indicate that QSM substantially improves the visibility of the PPN both in the atlas and individual images. Our findings indicate that the proposed SR network is an efficient tool for small-size brain nucleus identification. HR QSM is promising for improving the visibility of the PPN. The PPN can be directly identified on the individual QSM images acquired at the 3.0-T MR scanners, facilitating a direct targeting of PPN for DBS surgery.

The neural mechanisms underlying sevoflurane-induced loss of consciousness and recovery of consciousness after anaesthesia remain unknown. We investigated whether glutamatergic pedunculopontine tegmental nucleus (PPT) neurones are involved in the regulation of states of consciousness under sevoflurane anaesthesia. In vivo fibre photometry combined with electroencephalography (EEG)/electromyography recording was used to record changes in the activity of glutamatergic PPT neurones under sevoflurane anaesthesia. Chemogenetic and cortical EEG recordings were used to explore their roles in the induction of and emergence from sevoflurane anaesthesia. Optogenetic methods combined with EEG recordings were used to explore the roles of glutamatergic PPT neurones and of the PPT-ventral tegmental area pathway in maintenance of anaesthesia. The population activity of glutamatergic PPT neurones was reduced before sevoflurane-induced loss of righting reflex and gradually recovered after return of righting reflex. Chemogenetic inhibition of glutamatergic PPT neurones accelerated induction of anaesthesia (hM4Di-CNO vs mCherry-CNO, 76 [17] vs 121 [27] s, P <0.0001) and delayed emergence from sevoflurane anaesthesia (278 [98] vs 145 [53] s, P <0.0001) but increased sevoflurane sensitivity. Optogenetic stimulation of glutamatergic PPT neurons or of the PPT-ventral tegmental area pathway promoted cortical activation and behavioural emergence during steady-state sevoflurane anaesthesia, reduced the depth of anaesthesia, and caused cortical arousal during sevoflurane-induced EEG burst suppression. Glutamatergic PPT neurones regulate induction and emergence of sevoflurane anaesthesia. [ABSTRACT FROM AUTHOR]

The loss of midbrain dopaminergic (DA) neurons is the fundamental pathological feature of Parkinson’s disease (PD). PD causes chronic pain in two-thirds of patients. Recent studies showed that the activation of the pedunculopontine tegmental nucleus (PPTg) can effectively relieve inflammatory pain and neuropathic pain. The PPTg is located in the pontomesencephalic tegmentum, a target of deep brain stimulation (DBS) treatment in PD, and is involved in motor control and sensory integration. To test whether the lesion of midbrain DA neurons induced pain hypersensitivity, and whether the chemogenetic activation of the PPTg could modulate the pain, the AAV-hM3Dq receptor was transfected and expressed into the PPTg neurons of 6-hydroxydopamine-lesioned mice. In this study, von Frey, open field, and adhesive tape removal tests were used to assess animals’ pain sensitivity, locomotor activity, and sensorimotor function and somatosensory perception, respectively. Here, we found that the lesion of midbrain DA neurons induced a minor deficit in voluntary movement but did not affect sensorimotor function and somatosensory perception in the tape removal test. The results showed that lesion led to pain hypersensitivity, which could be alleviated both by levodopa and by the chemogenetic activation of the PPTg. Activating the PPTg may be a potential therapeutic strategy to relieve pain phenotypes in PD.

Vesicular glutamate transporters (VGLUTs) mediate the synaptic uptake of glutamate from the cytosol into synaptic vesicles and are considered unambiguous neurochemical markers of glutamate neurons. However, many neurons not classically thought of as glutamatergic also express a VGLUT and co-release glutamate. Using a genetic fate-mapping strategy we found that most cholinergic neurons in the mouse mesopontine tegmentum express VGLUT2 at some point during development, including the pedunculopontine tegmental nucleus (PPTg), laterodorsal tegmental nucleus, and parabigeminal nucleus (PBG), but not the oculomotor nucleus. In contrast, very few of these cholinergic neurons displayed evidence of vesicular GABA transporter expression. Using multiplex fluorescent in situ hybridization, we determined that only PBG cholinergic neurons are also predominantly positive for VGLUT2 mRNA in the adult, with only small numbers of PPTg cholinergic neurons overlapping with VGLUT2 mRNA. Using Cre-dependent viral vectors we confirm these in situ hybridization data, and demonstrate projection patterns of cholinergic and glutamatergic populations. These results demonstrate that most mesopontine cholinergic neurons may transiently express VGLUT2, but that a large majority of PBG neurons retain VGLUT2 expression throughout adulthood, and support a growing body of literature indicating that distinct cholinergic populations have differing potential for GABA or glutamate co-release.

The pedunculopontine tegmental nucleus (PPN) regulates the activity of dopaminergic cells in the ventral tegmental area (VTA). In this study, the role of opioid receptors (OR) in the PPN on motivated behaviors was investigated by using a model of feeding induced by electrical VTA-stimulation (Es-VTA) in rats (male Wistar; n = 91). We found that the OR excitation by morphine and their blocking by naloxone within the PPN caused a change in the analyzed motivational behavior and neuronal activation. The opioid injections into the PPN resulted in a marked, dose-dependent increase/decrease in latency to feeding response (FR), which corresponded with increased neuronal activity (c-Fos protein), in most of the analyzed brain structures. Morphine dosed at 1.25/1.5 µg into the PPN significantly reduced behavior induced by Es-VTA, whereas morphine dosed at 0.25/0.5 µg into the PPN did not affect this behavior. The opposite effect was observed after the naloxone injection into the PPN, where its lowest doses of 2.5/5.0 μg shortened the FR latency. However, its highest dose of 25.0 μg into the PPN nucleus did not cause FR latency changes. In conclusion, the level of OR arousal in the PPN can modulate the activity of the reward system. [ABSTRACT FROM AUTHOR]

Background The cardiovascular effects of nicotinic receptors of cholinergic system in the pedunculopontine tegmental nucleus (PPT) were shown. Objective In the following, the cardiovascular effects of the muscarinic receptor, another receptor in this system, were examined. Methods Rats were divided into eight groups: 1) control; 2 and 3) Ach (acetylcholine, an agonist) 90 and 150 nmol; 4 and 5) Atr (atropine; a muscarinic antagonist) 3 and 9 nmol; 6) Atr 3 + Ach 150; 7) Atr 9 + Ach 150; and 8) Atr 3 + hexamethonium (Hexa; 300 nmol) + Ach 150. After anesthesia, cannulation of the femoral artery was performed, and then the mean arterial pressure (MAP), systolic blood pressure (SBP), and heart rate (HR) were recorded using a power lab apparatus. Results Following drug microinjection, the maximum change (Δ) in MAP, SBP, and HR was calculated and analyzed. Both doses of Ach (90 and 150) significantly decreased ΔMAP and ΔSBP but could not change ΔHR. Neither of the doses of Atr significantly affected ΔMAP, ΔSBP, and ΔHR. Co-injection of Atr 3 + Ach 150 only increased ΔHR, but Atr 9 + Ach 150 decreased ΔMAP and ΔSBP than Ach 150 alone. The effect of the co-injection of Atr 9 + Hexa 300 + Ach 150 was also the same as the Atr 9 + Ach 150 group. Conclusion The present results revealed that cholinergic muscarinic receptors in the PPT have an inhibitory effect on MAP and SBP with no important effect on HR.

Objective(s): In the present study, the cardiovascular effects of glutamate NMDA receptor of the pedunculopontine tegmental nucleus (PPT) in normotensive and hydralazine (HLZ) hypotensive rats were evaluated. Materials and Methods: In the normotensive condition, MK-801(1 nmol; an NMDA receptor antagonist) and L-glutamate (L-Glu, 50 nmol an agonist) alone and together were microinjected into the nucleus using a stereotaxic device. In hypotensive condition, 2 min after induction of hypotension by HLZ (10 mg/kg, intravenous), drugs, same as in normotensive condition, were microinjected into the PPT. Recorded mean arterial pressure (MAP), systolic blood pressure (SBP), and heart rate (HR) were recorded throughout the experiment by a Power lab apparatus that was connected to a catheter inserted into the femoral arty. The cardiovascular changes (Δ) induced by microinjection drugs were computed and statistically analyzed.Results: In the normotensive condition, L-Glu significantly increased ΔMAP and ΔSBP (P

Rationale: Drug-induced potentiation of ventral tegmental area (VTA) glutamate signaling contributes critically to the induction of sensitization - an enhancement in responding to a drug following exposure which is thought to reflect neural changes underlying drug addiction. The laterodorsal tegmental nucleus (LDTg) provides one of several sources of glutamate input to the VTA. Objective: We used optogenetic techniques to test either the role of LDTg glutamate cells or their VTA afferents in the development of cocaine sensitization in male VGluT2::Cre mice. These were inhibited using halorhodopsin during each of five daily cocaine exposure injections. The expression of locomotor sensitization was assessed following a cocaine challenge injection 1-week later. Results: The locomotor sensitization seen in control mice was absent in male mice subjected to inhibition of LDTg-VTA glutamatergic circuitry during cocaine exposure. As sensitization of nucleus accumbens (NAcc) dopamine (DA) overflow is also induced by this drug exposure regimen, we used microdialysis to measure NAcc DA overflow on the test for sensitization. Consistent with the locomotor sensitization results, inhibition of LDTg glutamate afferents to the VTA during cocaine exposure prevented the sensitization of NAcc DA overflow observed in control mice. Conclusions: These data identify the LDTg as the source of VTA glutamate critical for the development of cocaine sensitization in male mice. Accordingly, the LDTg may give rise to the synapses in the VTA at which glutamatergic plasticity, known to contribute to the enhancement of addictive behaviors, occurs. [ABSTRACT FROM AUTHOR]

Parkinson’s disease, Multiple System Atrophy, and Lewy Body Dementia are incurable diseases called α-synucleinopathies as they are mechanistically linked to the protein, α-synuclein (α-syn). α-syn exists in different structural forms which have been linked to clinical disease distinctions. However, sleeping disorders (SDs) are common in the prodromal phase of all three α-synucleinopathies, which suggests that sleep-controlling neurons are affected by multiple forms of α-syn. To determine whether a structure-independent neuronal impact of α-syn exists, we compared and contrasted the cellular effect of three different α-syn forms on neurotransmitter-defined cells of two sleep-controlling nuclei located in the brainstem: the laterodorsal tegmental nucleus and the pedunculopontine tegmental nucleus. We utilized size exclusion chromatography, fluorescence spectroscopy, circular dichroism spectroscopy and transmission electron microscopy to precisely characterize ​​timepoints in the α-syn aggregation process with three different dominating forms of this protein (monomeric, oligomeric and fibril) and we conducted an in-depth investigation of the underlying neuronal mechanism behind cellular effects of the different forms of the protein using electrophysiology, multiple-cell calcium imaging, single-cell calcium imaging and live-location tracking with fluorescently-tagged α-syn. Interestingly, α-syn altered membrane currents, enhanced firing, increased intracellular calcium and facilitated cell death in a structure-independent manner in sleep-controlling nuclei, and postsynaptic actions involved a G-protein-mediated mechanism. These data are novel as the sleep-controlling nuclei are the first brain regions reported to be affected by α-syn in this structure-independent manner. These regions may represent highly important targets for future neuroprotective therapy to modify or delay disease progression in α-synucleinopathies. [ABSTRACT FROM AUTHOR]

The pedunculopontine nucleus (PPN) has been proposed as target for deep brain stimulation (DBS) in patients with postural instability and gait disorders due to its involvement in muscle tonus adjustments and control of locomotion. However, it is a deep-seated brainstem nucleus without clear imaging or electrophysiological markers. Some studies suggested that diffusion tensor imaging (DTI) may help guiding electrode placement in the PPN by showing the surrounding fiber bundles, but none have provided a direct histological correlation. We investigated DTI fractional anisotropy (FA) maps from in vivo and in situ post-mortem magnetic resonance images (MRI) compared to histological evaluations for improving PPN targeting in humans. A post-mortem brain was scanned in a clinical 3T MR system in situ. Thereafter, the brain was processed with a special method ideally suited for cytoarchitectonic analyses. Also, nine volunteers had in vivo brain scanning using the same MRI protocol. Images from volunteers were compared to those obtained in the post-mortem study. FA values of the volunteers were obtained from PPN, inferior colliculus, cerebellar crossing fibers and medial lemniscus using histological data and atlas information. FA values in the PPN were significantly lower than in the surrounding white matter region and higher than in areas with predominantly gray matter. In Nissl-stained histologic sections, the PPN extended for more than 10 mm in the rostro-caudal axis being closely attached to the lateral parabrachial nucleus. Our DTI analyses and the spatial correlation with histological findings proposed a location for PPN that matched the position assigned to this nucleus in the literature. Coregistration of neuroimaging and cytoarchitectonic features can add value to help establishing functional architectonics of the PPN and facilitate neurosurgical targeting of this extended nucleus.

The pedunculopontine tegmental (PPT) nucleus has long been implicated in the regulation of cortical activity and behavioral states, including rapid eye-movement (REM) sleep. For example, electrical stimulation of the PPT region during sleep leads to rapid awakening, whereas lesions of the PPT in cats reduce REM sleep. Though these effects have been linked with the activity of cholinergic PPT neurons, the PPT also includes intermingled glutamatergic and GABAergic cell populations, and the precise roles of cholinergic, glutamatergic, and GABAergic PPT cell groups in regulating cortical activity and behavioral state remain unknown. Using a chemogenetic approach in three Cre-driver mouse lines, we found that selective activation of glutamatergic PPT neurons induced prolonged cortical activation and behavioral wakefulness, whereas inhibition reduced wakefulness and increased non-REM (NREM) sleep. Activation of cholinergic PPT neurons suppressed lower-frequency electroencephalogram rhythms during NREM sleep. Last, activation of GABAergic PPT neurons slightly reduced REM sleep. These findings reveal that glutamatergic, cholinergic, and GABAergic PPT neurons differentially influence cortical activity and sleep/wake states.Significance statementMore than 40 million Americans suffer from chronic sleep disruption, and the development of effective treatments requires a more detailed understanding of the neuronal mechanisms controlling sleep and arousal. The pedunculopontine tegmental (PPT) nucleus has long been considered a key site for regulating wakefulness and REM sleep. This is mainly because of the cholinergic neurons contained in the PPT nucleus. However, the PPT nucleus also contains glutamatergic and GABAergic neurons that likely contribute to the regulation of cortical activity and sleep-wake states. The chemogenetic experiments in the present study reveal that cholinergic, glutamatergic, and GABAergic PPT neurons each have distinct effects on sleep/wake behavior, improving our understanding of how the PPT nucleus regulates cortical activity and behavioral states.

Dopamine transmission from midbrain ventral tegmental area (VTA) neurons underlies behavioral processes related to motivation and drug addiction. The pedunculopontine tegmental nucleus (PPTg) is a brainstem nucleus containing glutamate-, acetylcholine-, and GABA-releasing neurons with connections to basal ganglia and limbic brain regions. Here we investigated the role of PPTg glutamate neurons in reinforcement, with an emphasis on their projections to VTA dopamine neurons. We used cell-type-specific anterograde tracing and optogenetic methods to selectively label and manipulate glutamate projections from PPTg neurons in mice. We used anatomical, electrophysiological, and behavioral assays to determine their patterns of connectivity and ascribe functional roles in reinforcement. We found that photoactivation of PPTg glutamate cell bodies could serve as a direct positive reinforcer on intracranial self-photostimulation assays. Further, PPTg glutamate neurons directly innervate VTA; photostimulation of this pathway preferentially excites VTA dopamine neurons and is sufficient to induce behavioral reinforcement. These results demonstrate that ascending PPTg glutamate projections can drive motivated behavior, and PPTg to VTA synapses may represent an important target relevant to drug addiction and other mental health disorders.Significance statementUncovering brain circuits underlying reward-seeking is an important step toward understanding the circuit bases of drug addiction and other psychiatric disorders. The dopaminergic system emanating from the ventral tegmental area (VTA) plays a key role in regulating reward-seeking behaviors. We used optogenetics to demonstrate that the pedunculopontine tegmental nucleus sends glutamatergic projections to VTA dopamine neurons, and that stimulation of this circuit promotes behavioral reinforcement. The findings support a critical role for pedunculopontine tegmental nucleus glutamate neurotransmission in modulating VTA dopamine neuron activity and behavioral reinforcement.

The cardiovascular effects of nicotinic receptors of cholinergic system in the pedunculopontine tegmental nucleus (PPT) were shown. In the following, the cardiovascular effects of the muscarinic receptor, another receptor in this system, were examined. Rats were divided into eight groups: 1) control; 2 and 3) Ach (acetylcholine, an agonist) 90 and 150 nmol; 4 and 5) Atr (atropine; a muscarinic antagonist) 3 and 9 nmol; 6) Atr 3 + Ach 150; 7) Atr 9 + Ach 150; and 8) Atr 3 + hexamethonium (Hexa; 300 nmol) + Ach 150. After anesthesia, cannulation of the femoral artery was performed, and then the mean arterial pressure (MAP), systolic blood pressure (SBP), and heart rate (HR) were recorded using a power lab apparatus. Following drug microinjection, the maximum change (Δ) in MAP, SBP, and HR was calculated and analyzed. Both doses of Ach (90 and 150) significantly decreased ΔMAP and ΔSBP but could not change ΔHR. Neither of the doses of Atr significantly affected ΔMAP, ΔSBP, and ΔHR. Co-injection of Atr 3 + Ach 150 only increased ΔHR, but Atr 9 + Ach 150 decreased ΔMAP and ΔSBP than Ach 150 alone. The effect of the co-injection of Atr 9 + Hexa 300 + Ach 150 was also the same as the Atr 9 + Ach 150 group. The present results revealed that cholinergic muscarinic receptors in the PPT have an inhibitory effect on MAP and SBP with no important effect on HR. [ABSTRACT FROM AUTHOR]

The pedunculopontine tegmental nucleus (PPN) regulates the activity of dopaminergic cells in the ventral tegmental area (VTA). In this study, the role of opioid receptors (OR) in the PPN on motivated behaviors was investigated by using a model of feeding induced by electrical VTA-stimulation (Es-VTA) in rats (male Wistar; n = 91). We found that the OR excitation by morphine and their blocking by naloxone within the PPN caused a change in the analyzed motivational behavior and neuronal activation. The opioid injections into the PPN resulted in a marked, dose-dependent increase/decrease in latency to feeding response (FR), which corresponded with increased neuronal activity (c-Fos protein), in most of the analyzed brain structures. Morphine dosed at 1.25/1.5 µg into the PPN significantly reduced behavior induced by Es-VTA, whereas morphine dosed at 0.25/0.5 µg into the PPN did not affect this behavior. The opposite effect was observed after the naloxone injection into the PPN, where its lowest doses of 2.5/5.0 μg shortened the FR latency. However, its highest dose of 25.0 μg into the PPN nucleus did not cause FR latency changes. In conclusion, the level of OR arousal in the PPN can modulate the activity of the reward system.

• Single stimuli applied to the pedunculopontine tegmental nucleus (PPTg) modulate the blink reflex (BR) in Parkinson's disease. • The action of the PPTg on the BR differs from the action exerted by other basal ganglia nuclei. • The PPTg has a critical role in the pathway mediating the prepulse inhibition of the BR. To investigate the effects on the blink reflex (BR) of single stimuli applied to the pedunculopontine tegmental nucleus (PPTg). The BR was evoked by stimulating the supraorbital nerve (SON) in fifteen patients suffering from idiopathic Parkinson's disease (PD) who had electrodes monolaterally or bilaterally implanted in the PPTg for deep brain stimulation (DBS). Single stimuli were delivered to the PPTg through externalized electrode connection wires 3–4 days following PPTg implantation. PPTg stimuli increased the latency and reduced duration, amplitude and area of the R2 component of the BR in comparison to the response recorded in the absence of PPTg stimulation. These effects were independent of the side of SON stimulation and were stable for interstimulus interval (ISI) between PPTg prepulse and SON stimulus from 0 to 110 ms. The PPTg-induced prepulse inhibition of the BR was bilaterally present in the brainstem. The R1 component was unaffected. The prepulse inhibition of the R2 component may be modulated by the PPTg. These findings suggest that abnormalities of BR occurring in PD may be ascribed to a reduction of basal ganglia-mediated inhibition of brainstem excitability. [ABSTRACT FROM AUTHOR]

• Swallowing reflex (SR) was evoked by stimulation of the superior laryngeal nerve. • Stimulation of the pedunculopontine tegmental nucleus (PTg) suppressed the SR. • Microinjection of glutamate into the PTg suppressed the SR. • These results imply that the PTg is related to the control of swallowing. This study investigates whether the swallowing reflex is modulated by stimulation of the pedunculopontine tegmental nucleus (PTg). Sprague–Dawley rats under urethane anesthesia were used. The swallowing reflex was induced by electrical stimulation of the superior laryngeal nerve and was identified by the electromyographic activities from the mylohyoid muscle. The number of swallows was reduced by electrical stimulation of the PTg. The latency of the onset of the first swallow was increased during stimulation of the PTg. The duration of electromyogram bursts of the mylohyoid muscle was significantly shorter during the PTg stimulation than with no stimulation. The number of swallows was reduced, latency of onset of the first swallow increased, the duration of electromyogram bursts of the mylohyoid muscle was significantly shorter and the peak-to-peak amplitude of electromyogram bursts of the mylohyoid muscle was significantly suppressed after microinjection of glutamate into the PTg. These results suggest that the PTg is involved in the control of swallowing. [ABSTRACT FROM AUTHOR]

Background: Glutamate is an important excitatory neurotransmitter in the pedunculopontine tegmental (PPT) nucleus. The cardiovascular effect of glutamate and its non-N-methyl-D-aspartate (NMDA) receptor in the PPT is unknown; therefore, we evaluated glutamate and its non-NMDA receptor on cardiovascular parameters in normotensive and hypotensive induced by hydralazine (HLZ) in rat. Materials and Methods: After anesthesia, the femoral artery was cannulated for recording of cardiovascular parameters. Microinjection of drugs was done stereotaxically. L-Glutamate (L-Glu) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) (an antagonist of nonNMDA receptor) were microinjected into the PPT in normotensive and HLZ hypotensive rats. Changes (Δ) of mean arterial pressure (MAP), systolic blood pressure (SBP), and heart rate (HR) were obtained and compared with the control group. Results: In normotensive rats, L-Glu significantly increased SBP and MAP (P < 0.001) and decreased HR (P < 0.01), whereas CNQX alone did not significantly effect. Coinjection L-Glu + CNQX significantly attenuates the cardiovascular effect of L-Glu (P < 0.05 to P < 0.01). In hypotension induced by HLZ, SBP and MAP significantly decrease but HR did not change. In HLZ groups, L-Glu significantly improves (P < 0.05) and CNQX deteriorated hypotension induced by HLZ (P < 0.05). Coinjection of L-Glu + CNQX also attenuates the effect of L-Glu on Δ MAP and Δ SBP. In hypotension, ΔHR induced by L-Glu was significantly higher than CNQX (P < 0.01). In L-Glu + CNQX group, ΔHR also was lower than L-Glu (P < 0.05). Conclusion: Our findings revealed that glutamatergic system of the PPT in both normotensive and hypotension induced by HLZ plays a pressor with bradycardic responses that partly mediated by non-NMDA receptor.

Objective(s): Cholinergic neurons are important neurons in the Pedunculopontine tegmental nucleus (PPT). In this study, nicotinic receptor of the PPT in central cardiovascular regulation in the anesthetized rat was evaluated. Materials and Methods: Saline, acetylcholine (Ach; doses: 90 and 150 nmol), hexamethonium (Hexa; doses: 100 and 300 nmol) and higher doses of Hexa (300 nmol) + Ach (150 nmol) microinjected into the PPT. The femoral artery was cannulated and cardiovascular responses were continuously recorded by a power lab system. After injection of drugs, peak changes of mean arterial pressure (∆MAP), systolic blood pressure (∆SBP) and heart rate (∆HR) calculated and compared with saline group.Results: The ∆SBP and ∆MAP significantly decreased by two doses of Ach (PConclusion: These results indicate that nicotinic receptor of the PPT has an inhibitory effect on ∆HR with no significant effect on ∆MAP or ∆SBP.

Objective. To study the projections of individual subregions of the dorsal raphe nucleus (DRN) to functionally diverse areas of the basal ganglia in the dog brain. Materials and methods. A method based on the retrograde axonal transport of horseradish peroxidase (HRP) was used in 43 mongrel dogs given injections into functionally diverse areas of the basal ganglia to study the spatial organization of the projections from different parts of the DRN to these structures. At 48 h after perfusion of the brain, tetramethylbenzidine was used for the histochemical detection of HRP in DRN neurons in frontal serial sections of the brain and the numbers of labeled neurons in each area, as identified on serial frontal celloidin brain sections stained with toluidine, were counted under the microscope. Results. The spatial organization of projections to functionally diverse areas of the basal ganglia from individual functionally diverse parts of the DRN was studied in dogs using a method based on the retrograde axonal transport of HRP. The topographic characteristics of projection connections were identified, pointing to the possible segregated conduction of information from the dorsal part of the DRN, which has connections with limbic structures, i.e., limbic subareas of the corpus striatum. The overlapping of the terminal fields of neurons from all parts of the DRN receiving and sending functionally diverse information to the basal ganglia and structures connected to them seen in the entopeduncular nucleus, the ventral pallidum, the deep mesencephalic nucleus, and the medial part of the pedunculopontine nucleus of the tegmentum is evidence that this information may be integrated in these nuclei. The structural basis for information processing in the morphofunctional system of the basal ganglia was analyzed. Conclusions. Data are presented on the topographical organization of projections directed to functionally diverse areas of the basal ganglia from different parts of the DRN, providing evidence of the possible influences of different parts of the DRN on a wide spectrum of behavioral and physiological processes involving the basal ganglia. The connection system identified here is involved in conducting information and integrating it in the morphofunctional system of the basal ganglia and provides the structural basis for understanding the mechanisms of their functioning in health and disease. [ABSTRACT FROM AUTHOR]

• Chronic alcohol intake does not alter the number of PPT and LDT cholinergic neurons. • Alcohol withdrawal do not alter the number of PPT and LDT cholinergic neurons. • Chronic alcohol intake induces hypertrophy of PPT and LDT cholinergic neurons. • PPT and LDT cholinergic neurons remain hypertrophic 2 months after withdrawal. • Withdrawal from chronic ethanol intake induces structural changes in the PPT and LDT. The brain cholinergic system comprises two main recognized subdivisions, the basal forebrain and the brainstem cholinergic systems. The effects of chronic alcohol consumption on the basal forebrain cholinergic nuclei have been investigated extensively, but there is only one study that has examined those effects on the brainstem cholinergic nuclei. The last one comprises the pedunculopontine tegmental (PPT) and the laterodorsal tegmental (LDT) nuclei, which are known to give origin to the main cholinergic projection to the ventral tegmental area, a key brain region of the neural circuit, the mesocorticolimbic system, that mediates several behavioral and physiological processes, including reward. In the present study, we have examined, using stereological methods, the effects of chronic alcohol consumption (6 months) and subsequent withdrawal (2 months) on the total number and size of PPT and LDT choline acetyltransferase (ChAT)-immunoreactive neurons. The total number of PPT and LDT ChAT-immunoreactive neurons was unchanged in ethanol-treated and withdrawn rats. However, ChAT-immunoreactive neurons were significantly hypertrophied in ethanol-treated rats, an alteration that did not revert 2 months after ethanol withdrawal. These results show that prolonged exposure to ethanol leads to long-lasting, and potentially irreversible, cytoarchitectonic and neurochemical alterations in the brainstem cholinergic nuclei. These alterations suggest that the alcohol-induced changes in the brainstem cholinergic nuclei might play a role in the mechanisms underlying the development of addictive behavior to alcohol. [ABSTRACT FROM AUTHOR]

The combination of phasic and tonic neuromuscular processes are involved in the maintenance of normal upright posture. The latter is of particular importance in some pathologies, such as Parkinson's Disease (PD), which is known by one of its cardinal symptoms—tonic dysfunction (i.e., rigidity). Changes in tonic function may also occur during healthy aging. In this investigation, somatosensory input was manipulated by changing the support surface orientation for prolonged periods of quiet stance (QS). The aim was to shed light on how long-term tonic responses called postural lean after-effects are affected by aging and age-related neuropathology. Forty one participants were tested: 19 healthy young (25±5 years), 13 healthy older (63±8 years), and 9 adults with PD (63±5 years). Baseline conditions were eyes-closed QS on a stable surface or standing on an unstable, sway-referenced (SR) surface. Four experimental conditions combined two types of toes-up ramp tilt adaptation (120 s of toes-up static 7° tilt or sinusoidal 7° ± 3° tilt) with two types of post-adaptation (120 s of QS or SR). Results revealed postural after-effects during post-adaptation QS showing significant anterior COP shift for both young and older adults (p < 0.0001), but not PD (p > 0.06, n.s.). Compared to young, postural after-effects in older adults showed longer decay constants and did not return to baseline COP within the 120 s post-adaptation period (p < 0.05). Postural after-effects during SR, which appeared as toes-up surface tilt were highly significant in healthy populations (p = 0.001), but took longer to develop in PD. Younger adults showed significantly larger dorsiflexion (p < 0.01) and faster decay constants than older adults (p < 0.05). In summary, (1) postural after-effects decayed to baseline when post-tilt surface was stable but were retained and even grew larger post-adaptation in the SR surface conditions in all groups, (2) postural after-effects differed between healthy age groups, (3) PD showed less adaptation to surface changes. Differences in size and decay of after-effects between healthy and PD groups suggest tonic neuromuscular processes play a role in how adaptable postural control is to changing surface conditions and this is affected by healthy aging and basal ganglia function.

Active expiration (AE) is part of the breathing phase; it is conditional and occurs when we increase our metabolic demand, such as during hypercapnia, hypoxia, or exercise. The parafacial respiratory group (pFRG) is involved in AE. Data from the literature suggest that excitatory and the absence of inhibitory inputs to the pFRG are necessary to determine AE. However, the source of the inputs to the pFRG that trigger AE remains unclear. We show in adult urethane-anesthetized Wistar rats that the pharmacological inhibition of the medial aspect of the nucleus of the solitary tract (mNTS) or the rostral aspect of the pedunculopontine tegmental nucleus (rPPTg) is able to generate AE. In addition, direct inhibitory projection from the mNTS or indirect cholinergic projection from the rPPTg is able to contact pFRG to trigger AE. The inhibition of the mNTS or the rPPTg under conditions of high metabolic demand, such as hypercapnia (9 –10% CO2), did not affect the AE. The present results suggest for the first time that inhibitory sources from the mNTS and a cholinergic pathway from the rPPTg, involving M2/M4 muscarinic receptors, could be important sources to modulate and sustain AE. [ABSTRACT FROM AUTHOR]

• Role of glutamate receptors in the PPN on motivated behaviors. • Electrical stimulation was applied to the VTA to induce feeding response. • MK-801 injection in the PPN temporarily impairs the VTA-induced behavior. • NMDA injection in the PPN does not significantly changed the VTA-induced behavior. • Neuronal brain activity (TH+/c-Fos+) supported those results. The mesolimbic system, particularly the somatodendritic ventral tegmental area (VTA), is responsible for the positive reinforcing aspects of various homeostatic stimuli. In turn, the pedunculopontine tegmental nucleus (PPN) is anatomically and functionally connected with the VTA and substantia nigra (SN). In the present study, we investigated the role of glutamate receptors in the PPN in motivated behaviors by using a model of feeding induced by electrical stimulation of the VTA in male Wistar rats (n = 80). We found that injection of 2.5/5 µg dizocilpine (MK-801; NMDA receptor antagonist) to the PPN significantly reduced the feeding response induced by unilateral VTA-stimulation. This reaction was significantly impaired after local injection of MK-801 into the PPN in the ipsilateral rather than the contralateral hemisphere. After NMDA injection (2/3 µg) to the PPN we did not observe behavioral changes, only a trend of a lengthening/shortening of the latency to a feeding reaction at the highest dose of NMDA (3 µg). Immunohistochemical TH+/c-Fos+ analysis revealed a decrease in the number of TH+ cells in the midbrain (VTA-SN) in all experimental groups and altered activity of c-Fos+ neurons in selected brain structures depending on drug type (MK-801/NMDA) and injection site (ipsi-/contralateral hemisphere). Additionally, the pattern of TH+/c-Fos+ expression showed lateralization of feeding circuit functional connectivity. We conclude that the level of NMDA receptor arousal in the PPN regulates the activity of the midbrain dopaminergic cells, and the PPN-VTA circuit may be important in the regulation of motivational aspects of food intake. [ABSTRACT FROM AUTHOR]

Objective: In this study, we analyzed the inhibitory control on the trigemino-cervical reflex (TCR), and whether or not prepulse modulation (PPM) has an effect on TCR. Thus, we studied the PPM of TCR. We hypothesized that TCR would presumably be under the modulatory effect after the prepulse stimulus similar to blink reflex (BR). We also studied the recovery of TCR which was previously shown.Methods: We included 13 healthy individuals. All subjects underwent recordings of TCR, TCR-PPM, and recovery of TCR. For TCR-PPM, a subthreshold stimulus to second finger 50 or 100 ms before the test stimulus was applied. For recovery of TCR, two stimuli at the infraorbital nerve were applied at 300, 500, and 800 ms interstimulus intervals (ISIs).Results: There was an inhibition of bilateral late responses of TCR at the ISIs of both 50 ms and 100 ms. There was no change of latencies. Full recovery of TCR did not develop even at the ISI 800 ms.Discussion: We have provided an evidence for the TCR-PPM in healthy subjects for the first time in this study. The prepulse inhibition is attributed to the functions of the pedunculopontine tegmental nucleus. Our study provides a strong indication that there are connections between pedunculopontine tegmental nucleus and trigemino-cervical circuit, which produces TCR. [ABSTRACT FROM AUTHOR]

The combination of phasic and tonic neuromuscular processes are involved in the maintenance of normal upright posture. The latter is of particular importance in some pathologies, such as Parkinson's Disease (PD), which is known by one of its cardinal symptoms—tonic dysfunction (i.e., rigidity). Changes in tonic function may also occur during healthy aging. In this investigation, somatosensory input was manipulated by changing the support surface orientation for prolonged periods of quiet stance (QS). The aim was to shed light on how long-term tonic responses called postural lean after-effects are affected by aging and age-related neuropathology. Forty one participants were tested: 19 healthy young (25±5 years), 13 healthy older (63±8 years), and 9 adults with PD (63±5 years). Baseline conditions were eyes-closed QS on a stable surface or standing on an unstable, sway-referenced (SR) surface. Four experimental conditions combined two types of toes-up ramp tilt adaptation (120 s of toes-up static 7° tilt or sinusoidal 7° ± 3° tilt) with two types of post-adaptation (120 s of QS or SR). Results revealed postural after-effects during post-adaptation QS showing significant anterior COP shift for both young and older adults (p < 0.0001), but not PD (p > 0.06, n.s.). Compared to young, postural after-effects in older adults showed longer decay constants and did not return to baseline COP within the 120 s post-adaptation period (p < 0.05). Postural after-effects during SR, which appeared as toes-up surface tilt were highly significant in healthy populations (p = 0.001), but took longer to develop in PD. Younger adults showed significantly larger dorsiflexion (p < 0.01) and faster decay constants than older adults (p < 0.05). In summary, (1) postural after-effects decayed to baseline when post-tilt surface was stable but were retained and even grew larger post-adaptation in the SR surface conditions in all groups, (2) postural after-effects differed between healthy age groups, (3) PD showed less adaptation to surface changes. Differences in size and decay of after-effects between healthy and PD groups suggest tonic neuromuscular processes play a role in how adaptable postural control is to changing surface conditions and this is affected by healthy aging and basal ganglia function. [ABSTRACT FROM AUTHOR]

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.

Background and Objectives: People commonly report positive changes following stressful experiences (perceived posttraumatic growth; PPTG), yet whether PPTG validly reflects positive changes remains unestablished., Design and Methods: We tested the extent to which COVID-19 pandemic-related PPTG relates to positive changes in corresponding psychosocial resources in a national US sample participating in a five wave study (T1-T5), focusing here on T2-T5: n s = 712-860. We examined correlations between resource change (both latent and observed difference scores) and PPTG at each occasion and conducted structural equation models to separate occasion-specific and stable (traitlike) PPTG variance. We related changes in resources to occasion-specific and stable PPTG components., Results: Associations between change scores and occasion-specific PPTG were sparse, providing limited evidence of PPTG validity. Associations between change scores and stable PPTG tended to be positive and stronger than associations for occasion-specific PPTG., Discussion: Perceptions of growth were largely unrelated to experienced positive changes and thus appear to be largely illusory. However, a personality-like tendency to believe one grows from stressful experiences relates more strongly to actual resource growth. These results suggest that people are not accurate reporters of positive changes they experience and that interventions aimed at promoting post-traumatic growth may be premature.

Generalised tonic-clonic seizures, generated by abnormal neuronal hyper-activity, cause a significant and long-lasting increase in the nociceptive threshold. The pedunculopontine tegmental nucleus (PPTN) plays a crucial role in the regulation of seizures as well as the modulation of pain, but its role in postictal antinociceptive processes remains unclear. In the present study, we aimed to investigate the involvement of PPTN neurons in the postictal antinociception. Wistar rats had their tail-flick baseline recorded and were injected with ibotenic acid (1.0 μg/0.2 μL) into the PPTN, aiming to promote a local neurotoxic lesion. Five days after the neuronal damage, pentylenetetrazole (PTZ; 64 mg/kg) was intraperitoneally administered to induce tonic-clonic seizures. The tail-withdrawal latency was measured immediately after the seizures (0 min) and subsequently at 10-min intervals until 130 min after the seizures were induced pharmacologically. Ibotenic acid microinjected into the PPTN did not reduce the PTZ-induced seizure duration and severity, but it diminished the postictal antinociception from 0 to 130 min after the end of the PTZ-induced tonic-clonic seizures. These results suggest that the postictal antinociception depends on the PPTN neuronal cells integrity. [ABSTRACT FROM AUTHOR]

Objectives: To image the pedunculopontine tegmental nucleus (PPN), a deep brain stimulation (DBS) target for Parkinson disease, using MRI with validated results.Methods: This study used the MP2RAGE sequence with high resolution and enhanced grey-white matter contrast on a 7-T ultra-high-field MRI system to image the PPN as well as a diffusion spectrum imaging method on a 3-T MRI system to reconstruct the main fibre systems surrounding the PPN. The coordinates of the rostral and caudal PPN poles of both sides were measured in relation to the third and fourth ventricular landmarks on the 7-T image.Results: The boundary of the PPN was delineated, and showed morphology consistent with previous histological works. The main fibres around the PPN were reconstructed. The pole coordinate results combined with the fibre spatial relationships validate the imaging results.Conclusions: A practical protocol is provided to directly localise the PPN using MRI; the position and morphology of the PPN can be obtained and validated by locating its poles relative to two ventricular landmarks and by inspecting its spatial relationship with the surrounding fibre systems. This technique can be potentially used in clinics to define the boundary of the PPN before DBS surgery for treatment of Parkinson disease in a more precise and reliable manner.Key Points: • Combined information helps localise the PPN as a DBS target for PD patients • Scan the PPN at 7 T and measure its coordinates against different ventricular landmarks • Reconstruct the main fibres around the PPN using diffusion spectrum imaging. [ABSTRACT FROM AUTHOR]

The acoustic startle reflex (ASR) is a short and intense defensive reaction in response to a loud and unexpected acoustic stimulus. In the rat, a primary startle pathway encompasses three serially connected central structures: the cochlear root neurons, the giant neurons of the nucleus reticularis pontis caudalis (PnC), and the spinal motoneurons. As a sensorimotor interface, the PnC has a central role in the ASR circuitry, especially the integration of different sensory stimuli and brain states into initiation of motor responses. Since the basal ganglia circuits control movement and action selection, we hypothesize that their output via the substantia nigra (SN) may interplay with the ASR primary circuit by providing inputs to PnC. Moreover, the pedunculopontine tegmental nucleus (PPTg) has been proposed as a functional and neural extension of the SN, so it is another goal of this study to describe possible anatomical connections from the PPTg to PnC. Here, we made 6-OHDA neurotoxic lesions of the SN pars compacta (SNc) and submitted the rats to a custom-built ASR measurement session to assess amplitude and latency of motor responses. We found that following lesion of the SNc, ASR amplitude decreased and latency increased compared to those values from the sham-surgery and control groups. The number of dopamine neurons remaining in the SNc after lesion was also estimated using a stereological approach, and it correlated with our behavioral results. Moreover, we employed neural tract-tracing techniques to highlight direct projections from the SN to PnC, and indirect projections through the PPTg. Finally, we also measured levels of excitatory amino acid neurotransmitters in the PnC following lesion of the SN, and found that they change following an ipsi/contralateral pattern. Taken together, our results identify nigrofugal efferents onto the primary ASR circuit that may modulate motor responses. [ABSTRACT FROM AUTHOR]

The ventral tegmental area (VTA), a pivotal brain region of the mesocorticolimbic dopaminergic system, is substantially innervated and modulated by cholinergic projections from the pedunculopontine tegmental nucleus and laterodorsal tegmental nucleus. In this review, we focus mainly on the current findings on VTA cholinergic compositions and functions, including VTA cholinergic innervations and synaptic connectivity, acetylcholine receptor expression and functional characteristics, cholinergic modulation of neuronal activity and dopamine efflux, cholinergic modulation of VTA-mediated behaviors such as reward and addiction, stress and depression, locomotion, etc. Taken together, these findings indicate that cholinergic transmission to the VTA plays an important role in modulation of the VTA circuit, which is implicated in regulation of multiple behaviors. [ABSTRACT FROM AUTHOR]

In order to find out the possible earliest biomarkers of Parkinson’s disease (PD) cholinopathy, we followed the impact of bilateral pedunculopontine tegmental nucleus (PPT) lesion in rat on: the cortical and hippocampal sleep/wake states architectures, all sleep states related EEG microstructures, sleep spindles, the basal and stimulated locomotor activity. Sleep and basal locomotor activity in adult Wistar rats were followed during their inactive circadian phase, and throughout the same aging period. The bilateral PPT lesions were done by 0.1 M ibotenic acid (IBO) during the surgical procedure for implantation of the electroencephalographic (EEG) and electromyographic (EMG) electrodes for chronic sleep recording. The cholinergic neuronal loss was identified by NADPH – diaphorase histochemistry. After all sleep and behavioral recording sessions, the locomotor activity was stimulated by d-amphetamine (d-AMPH) and the neuronal activity of striatum was followed by c-Fos immunolabeling. Impaired cholinergic innervation from the PPT was expressed earlier as sleep disorder then as movement disorder, and it was the earliest and long-lasting at hippocampal and thalamo-cortical level, and followed by a delayed “hypokinesia”. This severe impact of a tonically impaired PPT cholinergic innervation was evidenced as the cholinergic interneuronal loss of the caudate putamen and as a suppressed c-Fos expression after stimulation by d-AMPH. In order how they occurred, the hippocampal non rapid eye movement (NREM) sleep disorder, altered high voltage sleep spindle (HVS) dynamics during rapid eye movement (REM) sleep in the hippocampus and motor cortex, and “hypokinesia” may serve as the biomarkers of PD cholinopathy onset and progression. [ABSTRACT FROM AUTHOR]

Objective To evaluate the feasibility of deep brain stimulation (DBS) and compare the potential of four DBS targets in rats for regulating bladder activity: the periaqueductal gray (PAG), locus coeruleus (LC), rostral pontine reticular nucleus (PnO), and pedunculopontine tegmental nucleus (PPTg). Methods A bipolar stimulating electrode was implanted. The effects of DBS on the inhibition and activation of micturition reflexes were investigated by using isovolumetric intravesical pressure recordings. Results PAG DBS at 2–2.5 V, PnO DBS at 2–2.5 V, and PPTg DBS at 1.75–2.5 V nearly completely inhibited reflexive isovolumetric bladder contractions. By contrast, LC DBS at 1.75 and 2 V slightly augmented reflexive isovolumetric bladder contractions in rats. DBSs on PnO and PPTg at higher intensities (2.5–5 V) demonstrated a higher success rate and larger contraction area evocation in activating bladder contractions in a partially filled bladder. DBS targeting the PPTg was most efficient in suppressing reflexive isovolumetric bladder contractions. Conclusion PPTg DBS demonstrated stable results and high potency for controlling bladder contractions. PPTg might be a promising DBS target for developing new neuromodulatory approaches for the treatment of bladder dysfunctions. Significance DBS could be a potential approach to manage bladder function under various conditions. [ABSTRACT FROM AUTHOR]

Opioids, such as morphine or heroin, increase forebrain dopamine (DA) release and locomotion, and support the acquisition of conditioned place preference (CPP) or self-administration. The most sensitive sites for these opioid effects in rodents are in the ventral tegmental area (VTA) and rostromedial tegmental nucleus (RMTg). Opioid inhibition of GABA neurons in these sites is hypothesized to lead to arousing and rewarding effects through disinhibition of VTA DA neurons. We review findings that the laterodorsal tegmental (LDTg) and pedunculopontine tegmental (PPTg) nuclei, which each contain cholinergic, GABAergic, and glutamatergic cells, are important for these effects. LDTg and/or PPTg cholinergic inputs to VTA mediate opioid-induced locomotion and DA activation via VTA M5 muscarinic receptors. LDTg and/or PPTg cholinergic inputs to RMTg also modulate opioid-induced locomotion. Lesions or inhibition of LDTg or PPTg neurons reduce morphine-induced increases in forebrain DA release, acquisition of morphine CPP or self-administration. We propose a circuit model that links VTA and RMTg GABA with LDTg and PPTg neurons critical for DA-dependent opioid effects in drug-naïve rodents. [ABSTRACT FROM AUTHOR]

The relationship between serotonin dysfunction and schizophrenia commenced with the discovery of the effects of lysergic acid diethylamide (LSD) that has high affinity for 5-HT 2A receptors. Activation of these receptors produces perceptual and behavioural changes such as illusions, visual hallucinations and locomotor hyperactivity. Using prepulse inhibition (PPI) of the acoustic startle, which is impaired in schizophrenia,we aimed to investigate:i) the existence of a direct and potentially inhibitory neural pathway between the inferior colliculus (IC) and the pedunculopontine tegmental nucleus (PPTg) involved in the mediation of PPI responses by a neural tract tracing procedure;ii) if the microinjection of the 5-HT 2A receptors agonist DOI in IC would activate neurons in this structure and in the PPTg by a c-Fos protein immunohistochemistry study;iii) whether the deficits in PPI responses, observed after the administration of DOI in the IC, could be prevented by the concomitant microinjection of the GABA A receptor antagonist bicuculline in the PPTg.Male Wistar rats were used in this study. An IC-PPTg reciprocated neuronal pathway was identified by neurotracing. The number of c-Fos labelled cells was lower in the DOI group in IC and PPTg, suggesting that this decrease could be due to the high levels of GABA in both structures. The concomitant microinjections of bicuculline in PPTg and DOI in IC prevented the PPI deficit observed after the IC microinjection of DOI. Our findings suggest that IC 5-HT 2A receptors may be at least partially involved in the regulation of inhibitory pathways mediating PPI response in IC and PPTg structures. • the neural tract tracing study evidenced an IC-PPTg reciprocated neuronal pathway. • DOI microinjection in IC induced PPI deficit and reduced Fos expression in PPTg. • 5-HT 2A receptors are present on IC GABAergic interneurons. • 5-HT 2A activation triggers the IC-PPTg inhibitory pathway inducing PPI deficit. • DOI microinjection in IC and bicuculline in PPTg prevente DOI-induced PPI deficit. [ABSTRACT FROM AUTHOR]