Cognitive Roles of Anterior and Posterior Pedunculopontine Tegmentum Subregions

The pedunculopontine tegmentum (PPT) is part of the mesopontine cholinergic system with distinct anterior and posterior subdivisions. With fast sensory input and descending connections to brainstem locomotor centers, we predict posterior PPT (pPPT) mediates prepulse inhibition of acoustic startle reflex, a form of sensorimotor gating that affects attentional processes. Similar to pPPT cholinergic projections to ventral tegmental area, we predict anterior PPT cholinergic input to substantia nigra regulates dopamine release in striatum, which is important for reinforcement learning. We lesioned the PPT bilaterally in male Sprague Dawley rats with ibotenic acid. Posterior cholinergic cell loss was significantly correlated with prepulse inhibition scores, consistent with our predictions for pPPT mediation of PPI. Anterior cholinergic cell loss was not correlated with performance in cued version of Morris water maze task, though lesions were likely insufficient. These results contribute to investigation of anterior vs. posterior PPT contribution to higher cognitive function

Thalamic neuromodulation and its implications for executive networks

The thalamus is a key structure that controls the routing of information in the brain. Understanding modulation at the thalamic level is critical to understanding the flow of information to brain regions involved in cognitive functions, such as the neocortex, the hippocampus, and the basal ganglia. Modulators contribute the majority of synapses that thalamic cells receive, and the highest fraction of modulator synapses is found in thalamic nuclei interconnected with higher order cortical regions. In addition, disruption of modulators often translates into disabling disorders of executive behavior. However, modulation in thalamic nuclei such as the midline and intralaminar groups, which are interconnected with forebrain executive regions, has received little attention compared to sensory nuclei. Thalamic modulators are heterogeneous in regards to their origin, the neurotransmitter they use, and the effect on thalamic cells. Modulators also share some features, such as having small terminal boutons and activating metabotropic receptors on the cells they contact. I will review anatomical and physiological data on thalamic modulators with these goals: first, determine to what extent the evidence supports similar modulator functions across thalamic nuclei; and second, discuss the current evidence on modulation in the midline and intralaminar nuclei in relation to their role in executive function

Nicotine has a Direct Effect on Brainstem Startle-Mediating Neurons

Individuals with schizophrenia have impairments in prepulse inhibition of startle (PPI) which correlates with cognitive deficits. Nicotine improves the performance of patients and healthy individuals with PPI deficits on PPI tests. We hypothesized that nicotine directly affect startle-mediating neurons of the caudal pontine recticular nucleus (PnC) of the brainstem using electrophysiological recordings. The data revealed that nicotine (10 pM) increases leak current amplitude, reduces membrane resistance, and depolarizes the resting membrane potential. Nicotine had no significant effect on the EPSC amplitude for neither the trigeminal nor auditory stimulations. All effects were reversed only by a high dose (10 pM) of the a-j nAChR antagonist MLA and a low dose of TMPH (lOOnM; antagonizes all but the a7 nAChR). The effect of nicotine persisted in the presence of cadmium (100 pM), which blocks synaptic transmission. These results confirm the functional expression of nAChRs in the PnC and suggest a role of nAChRs in modulating startle responses directly in the brainstem

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 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 Role of Cholinergic Neurotransmission in Sensory Filtering and Sensorimotor Gating

At every moment, our brain is bombarded with sensory information. How we filter and process sensory information is critical for daily functioning and cognition. Examples of sensory filtering include habituation (a progressive decrease in responding) and prepulse inhibition (PPI, gating of responding). Our aim is to understand the differential role acetylcholine (ACh) plays in these processes. To study this we used both reflexive (acoustic startle response: ASR) and non-reflexive (locomotor) behaviours. PPI is hypothesized to occur via inhibitory cholinergic projections from the Pedunculopontine Tegmental Nucleus (PPT) to the startle pathway. The role of ACh in habituation of reflexive and non-reflexive behaviours is controversial. We found that, contrary to the predictions of the field, ACh modulated, not mediated, PPI. There was no impairment of PPI in cholinergic deficient mice. When we inhibited PPT cholinergic neurons using DREADDs we did not detect an impairment of PPI. Likewise, we were unable to induce PPI by optogenetic activation of these neurons. Instead we found that cholinergic function is critical for long-term habituation (decrement occurring across days) as cholinergic deficient mice showed an impairment which was rescued by galantamine. Furthermore, inhibition of PPT cholinergic cells decreased startle magnitude, whereas optogenetic activation of cholinergic PPT neurons increased startle. This demonstrates that these neurons are critical for regulating startle reactivity. Despite modulating reflexive behaviours, PPT cholinergic inhibition did not impact habituation of locomotion, re-affirming differential regulation of habituation of reflexive and non-reflexive behaviours. To uncover which cholinergic receptor type mediates effects on PPI and habituation we used an α7-nicotinic acetylcholine receptor (nAChR) knock-out mouse. These mice displayed a mild impairment of PPI, and no enhancement of startle magnitude or PPI via nicotine. This suggests ACh modulates PPI through this receptor, and confirms that cholinergic function enhances startle. Of interest, optogenetic enhancement of startle was blocked by nAChR antagonism. In conclusion, we demonstrate that ACh modulates PPI through α7-nAChRs and that ACh is critical for regulating startle reactivity, indicating a potential role in long-term habituation or sensitization of startle. In contrast to the common view, cholinergic PPT function does not inhibit startle, ruling out a mechanistic role in PPI

Nicotinic mechanisms mediating prepulse inhibition of the acoustic startle response (Spine title: Nicotinic mechanisms mediating PPI of the startle response)

Prepulse inhibition (PP1) is the attenuation of a startle response brought-on by a non-startling sensory stimulus (prepulse) presented 5-1000ms before the startle-evoking stimulus. It is a measure of sensory gating that is seen disrupted in schizophrenia, and other mental disorders. Nicotinic acetylcholine receptors (nAChRs) have been implicated in PPI of acoustic startle at both a systemic level and at the level in which the primary startle pathway can receive modulatory input - the caudal pontine reticular nucleus (PnC). This research will help clarify the role that nicotine plays in PPI at both a systemic level and at a level of the PnC. We show that the systemic effect of nicotine is at least partly mediated by non-PnC a7 nAChRs, and that the effect of nicotine in the PnC is mainly mediated by non-a7 nAChRs (likely a4p2 nAChRs). This research helps clarify the role that nicotine plays in sensorimotor gating, and may help in drug development in schizophrenia

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

Autism as a disorder of neural information processing: directions for research and targets for therapy

The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which theyfeed, is hampered bythe large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself