Cortical Cholinergic System Research Articles

Cholinergic dysregulation in prodromal Alzheimer’s disease

The cholinergic hypothesis of geriatric memory dysfunction led to the development of FDA-approved anticholinesterase drugs to maintain this system in AD patients. The importance of defining the status of the cholinergic basal forebrain cortical projection system in subjects with prodromal AD who are at risk for developing AD continues to be of great clinical and translational interest. The findings presented are derived from molecular and cellular neuropathologic investigations of people who died with a premortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI) and Alzheimer's disease (AD) as well as from AD transgenic animal studies. Clinical pathologic investigations revealed that CBF neurons maintain their cholinergic neuronal phenotype despite exhibiting pretangles, which correlate with cognitive impairment and an altered ratio of 3 repeat to 4 repeat tau in the MCI brain. Interestingly, the cortical cholinergic system displays an upregulation of choline acetyltransferease (ChAT) activity in the frontal cortex and hippocampus suggesting early reparative mechanisms during prodromal AD. Moreover, despite the early accumulation of amyloid burden in the precuneus component of the default memory network, cholinergic enzyme activity remains stable in MCI and only declines in clinical AD, when PiB binding and soluble beta-amyloid 42 levels are substantially elevated compared to MCI. Moreover, amyloid deposition failed to induce cholinergic cortical neuronal degeneration in APP and triple transgenic mouse models of AD. Increased cortical levels of proNGF and a decrease in TrkA suggest a shift away from cell survival to apoptotic proNGF signaling. Interestingly, this switch to cell death mechanisms did not occur in the hippocampus during prodromal AD. Together these data suggest that CBF system dysregulation is not uniform, the system is neuroplastic, pretangle pathology plays a key role in cognitive impairment, amyloid deposition may not be toxic early on and there is a shift from cell survival to cell death trophic factor signaling in MCI.

Time to pay attention: attentional performance time-stamped prefrontal cholinergic activation, diurnality, and performance.

Although the impairments in cognitive performance that result from shifting or disrupting daily rhythms have been demonstrated, the neuronal mechanisms that optimize fixed-time daily performance are poorly understood. We previously demonstrated that daily practice of a sustained attention task (SAT) evokes a diurnal activity pattern in rats. Here, we report that SAT practice at a fixed time produced practice time-stamped increases in prefrontal cholinergic neurotransmission that persisted after SAT practice was terminated and in a different environment. SAT time-stamped cholinergic activation occurred regardless of whether the SAT was practiced during the light or dark phase or in constant-light conditions. In contrast, prior daily practice of an operant schedule of reinforcement, albeit generating more rewards and lever presses per session than the SAT, neither activated the cholinergic system nor affected the animals' nocturnal activity pattern. Likewise, food-restricted animals exhibited strong food anticipatory activity (FAA) and attenuated activity during the dark phase but FAA was not associated with increases in prefrontal cholinergic activity. Removal of cholinergic neurons impaired SAT performance and facilitated the reemergence of nocturnality. Shifting SAT practice away from a fixed time resulted in significantly lower performance. In conclusion, these experiments demonstrated that fixed-time, daily practice of a task assessing attention generates a precisely practice time-stamped activation of the cortical cholinergic input system. Time-stamped cholinergic activation benefits fixed-time performance and, if practiced during the light phase, contributes to a diurnal activity pattern.

Impact of the NGF Maturation and Degradation Pathway on the Cortical Cholinergic System Phenotype

Cortical cholinergic atrophy plays a significant role in the cognitive loss seen with aging and in Alzheimer's disease (AD), but the mechanisms leading to it remain unresolved. Nerve growth factor (NGF) is the neurotrophin responsible for the phenotypic maintenance of basal forebrain cholinergic neurons in the mature and fully differentiated CNS. In consequence, its implication in cholinergic atrophy has been suspected; however, no mechanistic explanation has been provided. We have previously shown that the precursor of NGF (proNGF) is cleaved extracellularly by plasmin to form mature NGF (mNGF) and that mNGF is degraded by matrix metalloproteinase 9. Using cognitive-behavioral tests, Western blotting, and confocal and electron microscopy, this study demonstrates that a pharmacologically induced chronic failure in extracellular NGF maturation leads to a reduction in mNGF levels, proNGF accumulation, cholinergic degeneration, and cognitive impairment in rats. It also shows that inhibiting NGF degradation increases endogenous levels of the mature neurotrophin and increases the density of cortical cholinergic boutons. Together, the data point to a mechanism explaining cholinergic loss in neurodegenerative conditions such as AD and provide a potential therapeutic target for the protection or restoration of this CNS transmitter system in aging and AD.

Pre- and post-synaptic cortical cholinergic deficits are proportional to amyloid plaque presence and density at preclinical stages of Alzheimer’s disease

Amyloid imaging has identified cognitively normal older people with plaques as a group possibly at increased risk for developing Alzheimer's disease-related dementia. It is important to begin to thoroughly characterize this group so that preventative therapies might be tested. Existing cholinotropic agents are a logical choice for preventative therapy as experimental evidence suggests that they are anti-amyloidogenic and clinical trials have shown that they delay progression of mild cognitive impairment to dementia. A detailed understanding of the status of the cortical cholinergic system in preclinical AD is still lacking, however. For more than 30years, depletion of the cortical cholinergic system has been known to be one of the characteristic features of AD. Reports to date have suggested that some cholinergic markers are altered prior to cognitive impairment while others may show changes only at later stages of dementia. These studies have generally been limited by relatively small sample sizes, long postmortem intervals and insufficient definition of control and AD subjects by the defining histopathology. We, therefore, examined pre- and post-synaptic elements of the cortical cholinergic system in frontal and parietal cortex in 87 deceased subjects, including non-demented elderly with and without amyloid plaques as well as demented persons with neuropathologically confirmed AD. Choline acetyltransferase (ChAT) activity was used as a presynaptic marker while displacement of (3)H-pirenzepine binding by oxotremorine-M in the presence and absence of GppNHp was used to assess postsynaptic M1 receptor coupling. The results indicate that cortical ChAT activity as well as M1 receptor coupling are both significantly decreased in non-demented elderly subjects with amyloid plaques and are more pronounced in subjects with AD and dementia. These findings confirm that cortical cholinergic dysfunction in AD begins at the preclinical stage of disease and suggest that cholinotropic agents currently used for AD treatment are a logical choice for preventative therapy.

Phasic acetylcholine release and the volume transmission hypothesis: time to move on

Traditional descriptions of the cortical cholinergic input system focused on the diffuse organization of cholinergic projections and the hypothesis that slowly changing levels of extracellular acetylcholine (ACh) mediate different arousal states. The ability of ACh to reach the extrasynaptic space (volume neurotransmission), as opposed to remaining confined to the synaptic cleft (wired neurotransmission), has been considered an integral component of this conceptualization. Recent studies demonstrated that phasic release of ACh, at the scale of seconds, mediates precisely defined cognitive operations. This characteristic of cholinergic neurotransmission is proposed to be of primary importance for understanding cholinergic function and developing treatments for cognitive disorders that result from abnormal cholinergic neurotransmission.

NGF-Cholinergic Dependency in Brain Aging, MCI and Alzheimers Disease

Forebrain cholinergic neurons are highly dependent on nerve growth factor (NGF) for phenotype maintenance. We have established that in addition to "target-derived" NGF neurotrophic stimulation, cholinergic neurons also respond dose-dependently, to intra-parenchymal NGF administration in the somato-dendritic region of the nucleus Basalis, thus illustrating the potential of alternative reparative therapies which would by-pass the undesirable effects of diffuse neurotrophin application. Moreover, our lab has also observed that the steady-state number of cortical cholinergic synapses is dependent on continuous NGF supply, as anti-NGF monoclonal antibodies and TrkA receptor antagonists deplete pre-existing cholinergic bouton numbers. Furthermore, the application of either NGF or TrkA NGF-mimetic agonists successfully rescues the age-dependent loss of cortical cholinergic boutons in aged-impaired rats. The vulnerability of the cortical cholinergic system has also been demonstrated in transgenic animal models of the Alzheimer's disease (AD) amyloid pathology. It is of interest to note however, that an up-regulation of cholinergic presynaptic boutons has been observed in certain transgenic mouse models prior to plaque formation. This observation is similar to the visibly increased immunoreactivity of cortical and hippocampal choline acetyltransferase (ChAT) fibers in patients with Mild Cognitive Impairment (MCI). A series of ex-vivo experiments conducted by our group have demonstrated that contrary to popular belief, proNGF, as opposed to mature NGF, is released from the cerebral cortex in an activity-dependent manner. In addition, proNGF appears to be released with a series of pro-enzymes and enzymes, which are involved in its subsequent maturation to NGF and degradation in the extracellular space. Given that proNGF is known to be upregulated in AD patients a dysregulation in the maturation or degradation of mature NGF might explain the preferential vulnerability of the cholinergic system in the AD pathology.

Short latency afferent inhibition is not impaired in mild cognitive impairment

Objective To determine whether cortical cholinergic circuit impairment exists in the mild cognitive impairment (MCI) brain. Methods Fifteen healthy elderly controls (NC), 16 amnesic MCI subjects and 12 probable Alzheimer’s disease (AD) subjects were recruited. Conditioning stimuli were delivered at the right wrist followed by test transcranial magnetic stimulation (TMS) of the left motor cortex. The center of the linear contiguous segment of the coil was placed over a point 5 cm lateral to the vertex on the interaural line. The interstimulus intervals (ISIs) between the conditioning stimuli and the test stimuli were set at 20, 40, 100, 200 and 600 ms. An inhibitory effect that occurred at ISIs as short as 20 ms was defined as short-latency afferent inhibition (SAI). Results SAI was significantly reduced in subjects with AD compared with NC, but it was not reduced in subjects with MCI. Conclusions A difference in cortical excitability between subjects with AD and subjects with MCI could be captured by an in vivo neurophysiological method. Significance The state of the neurotransmitter systems, including the cortical cholinergic system, is thought by some compensatory mechanisms to be kept at the normal level in subjects with MCI.

Cholinergic control of attention to cues guiding established performance versus learning: Theoretical comment on Maddux, Kerfoot, Chatterjee, and Holland (2007).

Previous views on the cognitive functions of the basal forebrain cholinergic system often suggested that this neuromodulator system influences fundamental attentional processes but not learning. The results from an elegant series of studies by J. M. Maddux, E. C. Kerfoot, S. Chatterjee, and P. Holland reveal the intricate relationships between the levels of attentional processing of stimuli and the rate of learning about such stimuli. Moreover, their results indicate a double dissociation between the role of prefrontal and posterior parietal cholinergic inputs, respectively, in attentional performance and the learning rate of stimuli that command different levels of attentional processing. Separate yet interacting components of the cortical cholinergic input system modulate the attentional processing of cues that guide well-practiced performance or that serve as conditioned stimuli during learning.

Cholinergic influences on feature binding.

The binding problem refers to the fundamental challenge of the central nervous system to integrate sensory information registered by multiple brain regions to form a unified neural representation of a stimulus. Human behavioral, neuropsychological, and functional neuroimaging evidence suggests a fundamental role for attention in feature binding; however, its neurochemical basis is currently unknown. This study examined whether acetylcholine (ACh), a neuromodulator that has been implicated in attentional processes, plays a critical role in feature binding. Using a within-subjects pharmacological design and the cholinergic muscarinic antagonist scopolamine, the present experiments demonstrate, in a rat model, a critical role for the cortical muscarinic cholinergic system in feature binding. Specifically, ACh and the attentional resources that it supports are essential for the initial feature binding process but are not required to maintain neural representations of bound stimuli.

Glutamate receptors in nucleus accumbens mediate regionally selective increases in cortical acetylcholine release

The basal forebrain cortical cholinergic system (BFCS) is critical for the regulation of attentional information processing. BFCS activity is regulated by several cortical and subcortical structures, including the nucleus accumbens (NAC) and prefrontal cortex (PFC). GABAergic projection neurons from NAC to basal forebrain are modulated by Glu receptors within NAC. We previously reported that intra-NAC perfusions of NMDA or its antagonist CPP stimulate ACh release in PFC. In this experiment we determined whether this trans-synaptic modulation of cortical ACh release is evident in multi-sensory associational areas like the posterior parietal cortex (PPC). Artificial cerebrospinal fluid (aCSF, control), NMDA (250 or 400 muM), or CPP (200 or 400 muM) were perfused into the NAC shell and ACh was measured in the ipsilateral PPC. Amphetamine (2.0 mg/kg, i.p), was systemically administered as a positive control in a fourth session, since it also stimulates cortical ACh release but via mechanisms known to not necessitate transmission within the NAC. Neither NMDA nor CPP increased ACh efflux in the PPC, yet both drugs increased ACh release in PFC, suggesting that NMDA receptor modulation in the NAC increases ACh in the cortex in a regionally-specific manner. Systemic amphetamine administration significantly increased (100-200%) ACh in the PPC, suggesting that levels of ACh in the PPC can be increased following certain pharmacological manipulations. The cortical region-specific modulation of ACh by NAC may underlie the linkage of motivational information with top-down controls of attention as well as guide appropriate motor output following exposure to salient and behaviorally relevant stimuli.

Lack of Enhanced Effect of Antipsychotics Combined With Fluvoxamine on Acetylcholine Release in Rat Prefrontal Cortex

We have shown that coadministration of sulpiride and fluvoxamine preferentially increases the release of dopamine in the prefrontal cortex. To study the possible role of the cortical cholinergic system in this effect, we combined several other antipsychotic drugs with fluvoxamine and examined the effects on acetylcholine release in rat prefrontal cortex. Risperidone and clozapine significantly increased the release of acetylcholine but sulpiride did not, and fluvoxamine did not enhance the effects of the antipsychotics. These results further support the previous suggestion that the cortical dopamine system plays an important role in the effects of antipsychotic drugs administered in combination with fluvoxamine.

Microsphere embolism‐induced cortical cholinergic deafferentation and impairments in attentional performance

Ischemic events have been hypothesized to play a critical role on the pathogenesis of dementia and the acceleration of cognitive impairments. This experiment was designed to determine the consequences of microvascular ischemia on the cortical cholinergic input system and associated attention capacities. Injections of microspheres ( approximately 50 microm diameter; approximately 5000 microspheres/100 microL) into the right common carotid artery of rats served as a model of microvascular ischemia and resulted in decreases in the density of cholinergic fibers in the ipsilateral medial prefrontal cortex and frontoparietal areas. Furthermore, dense astrogliosis, indicated by glial fibrillary acidic protein (GFAP) immunohistochemistry, was observed in the globus pallidus, including the areas of origin of cholinergic projections to the cortex. Fluoro-Jade B staining indicated that loss of neurons in the cortex was restricted to areas of microsphere-induced infarcts. Attentional performance was assessed using an operant sustained attention task; performance in this task was previously demonstrated to reflect the integrity and activity of the cortical cholinergic input system. Embolized animals' performance was characterized by a decrease in the animals' ability to detect signals. Their performance in non-signal trials remained unaffected. The residual density of cholinergic axons in prefrontal and frontoparietal areas correlated with the animals' performance. The present data support the hypothesis that microvascular ischemia results in loss of cortical cholinergic inputs and impairs associated attentional performance. Microsphere embolism represents a useful animal model for studying the role of interactions between microvascular disorder and impaired forebrain cholinergic neurotransmission in the manifestation of cognitive impairments.

Augmented Prefrontal Acetylcholine Release during Challenged Attentional Performance

Previous research has demonstrated that attentional performance depends on the integrity of the cortical cholinergic input system and that such performance is associated with increases in cortical acetylcholine (ACh) release. The present experiment tested the hypothesis that the attentional impairments produced by bilateral basal forebrain infusions of the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV) are associated with attenuation of performance-associated increases in ACh release. Rats were trained in a sustained attention task and equipped with three guide cannula for the bilateral infusion of the NMDA receptor antagonist APV (0, 3, 20 nmol) and for the insertion of a dialysis probe into the medial prefrontal cortex (mPFC). APV or vehicle was infused remotely following completion of the first of five blocks of trials. During the first block, attentional performance was associated with a 140% increase in ACh efflux. Infusions of APV decreased the animals' ability to detect signals and augmented the increases in ACh efflux observed prior to infusions. These data indicate a dissociation between levels of attentional performance and increases in mPFC ACh release. Augmentation of performance-associated increases in mPFC cholinergic transmission is hypothesized to mediate the increased demands on attentional 'effort' that are required to maintain performance under challenging conditions.

Cholinergic cortical circuits in Parkinson’s disease and in progressive supranuclear palsy: a transcranial magnetic stimulation study

To investigate the involvement of the cortical cholinergic system in patients with Parkinson's disease (PD) and with progressive supranuclear palsy (PSP), we performed a comparative study of the short latency afferent inhibition (SAI) in ten patients with PD, in eight patients with PSP and in 15 healthy subjects. Six of the PD patients and four of the PSP patients had dementia. SAI was significantly increased in the PD patients, whereas it was not significantly different between PSP patients and the normal controls. Our findings demonstrate that the excitability of the motor cortex is differentially modulated by sensory afferents in PD and PSP and may indicate that the mechanisms of cholinergic dysfunction are different between the two diseases.

Cortical Cholinergic Transmission and Cortical Information Processing in Schizophrenia

Models of the neuronal mediation of psychotic symptoms traditionally have focused on aberrations in the regulation of mesolimbic dopaminergic neurons, via their telencephalic afferent connections, and on the impact of abnormal mesolimbic activity for functions of the ventral striatum and its pallidal-thalamic-cortical efferent circuitry. Repeated psychostimulant exposure models major aspects of the sensitized activity of ventral striatal dopaminergic transmission that is observed in patients exhibiting psychotic symptoms. Based on neuroanatomical, neurochemical, and behavioral data, the hypothesis that an abnormally reactive cortical cholinergic input system represents a necessary correlate of a sensitized mesolimbic dopaminergic system is discussed. Moreover, the abnormal cognitive mechanisms that contribute to the development of psychotic symptoms are attributed specifically to the aberrations in cortical cholinergic transmission and to its consequences on the top-down regulation of sensory and sensory-associational input functions. Experimental evidence from studies demonstrating repeated amphetamine-induced sensitization of cortical cholinergic transmission and the ability of antipsychotic drugs to normalize the activity of cortical cholinergic inputs, and from experiments indicating the attentional consequences of manipulations that increase the excitability of cortical cholinergic inputs, supports this hypothesis. Relevant human neuropathological and psychopharmacological data are discussed, and the implications of an abnormally regulated cortical cholinergic input system for pharmacological treatment strategies are addressed. Given the role of cortical cholinergic inputs in gating cortical information processing, even subtle changes in the regulation of this cortexwide input system that represent a necessary transsynaptic consequence of sensitized mesolimbic dopaminergic transmission profoundly contribute to the neuronal mediation of psychotic symptoms.

Effects of neonatal ventral hippocampal lesion in rats on stress‐induced acetylcholine release in the prefrontal cortex

Excitotoxic neonatal ventral hippocampus (NVH) lesions in rats result in characteristic post-pubertal hyper-responsiveness to stress and cognitive abnormalities analogous to those described in schizophrenia and suggestive of alterations in dopamine (DA) neurotransmission. Converging lines of evidence also point to dysfunctions in the cortical cholinergic system in neuropsychiatric disorders. In previous studies, we observed alterations in dopaminergic modulation of acetylcholine (Ach) release in the prefrontal cortex (PFC) in post-pubertal NVH-lesioned rats. These two neurotransmitter systems are involved in the stress response as PFC release of DA and Ach is enhanced in response to some stressful stimuli. As adult NVH-lesioned rats are behaviorally more reactive to stress, we investigated the effects of NVH lesions on tail-pinch stress-induced Ach and DA release in the PFC. Using in vivo microdialysis, we observed that tail-pinch stress resulted in significantly greater increases in prefrontal cortical Ach release in post-pubertal NVH-lesioned rats (220% baseline) compared with sham-operated controls (135% baseline). Systemic administration of the D1-like receptor antagonist SCH 23390 (0.5 mg/kg i.p.) or the D2-like receptor antagonist haloperidol (0.2 mg/kg i.p.), as well as intra-PFC administration of the D2-like antagonist sulpiride (100 microm), reduced stress-induced Ach release in PFC of adult NVH-lesioned rats. By contrast, intra-PFC administration of SCH 23390 (100 microm) failed to affect stress-induced Ach release in PFC of NVH-lesioned rats. Interestingly, using in vivo voltammetry, stress-induced stimulation of PFC DA release was found to be attenuated in adult NVH-lesioned rats. Taken together, these data suggest developmentally specific reorganization of prefrontal cortical cholinergic innervation notably regarding its regulation by DA neurotransmission.

Cortical Cholinergic Function and Deficits in Visual Attentional Performance in Rats Following 192 IgG-Saporin-induced Lesions of the Medial Prefrontal Cortex

Lesions of the basal forebrain (BF) cortical cholinergic system impair performance on a rodent five-choice visual attentional task. This study examines the effects on the same task of selective depletion of acetylcholine from the prefrontal cortex (PFC) using 192 IgG-saporin, the cholinergic immunotoxin. Rats were trained to detect brief visual stimuli, either presented unpredictably both temporally and spatially to increase attentional load, or under less demanding conditions where stimuli were temporally and spatially predictable. Following training, 192 IgG-saporin (50 ng or 100 ng/infusion) or its vehicle was infused bilaterally into the ventromedial PFC. The 100 ng lesion group exhibited post-operatively a transient increase in perseveration, specifically when the visual stimuli were temporally unpredictable. A vigilance decrement, as well as a reinstatement of perseverative responding occurred in both lesion groups under conditions of enhanced attentional load, specifically with high target frequency sustained over many trials. Lesioned subjects were also more impulsive with increased anticipatory errors. Systemic administration of the muscarinic receptor antagonist scopolamine further dissociated the groups with attentional accuracy in the 100 ng group decreasing relative to shams. These findings are consistent with an important modulatory influence of PFC function by BF cholinergic neurons, particularly during increased attentional demand.

Alterations in dopaminergic modulation of prefrontal cortical acetylcholine release in post‐pubertal rats with neonatal ventral hippocampal lesions

Excitotoxic lesion of the ventral hippocampus in neonatal rats is a putative animal model of schizophrenia with characteristic developmental abnormalities in dopaminergic neurotransmission and prefrontal cortical functions. Converging evidence also points to the involvement of the central cholinergic system in neuropsychiatric disorders. These two neurotransmitter systems are interlinked in the prefrontal cortex (PFC) where dopamine stimulates acetylcholine (ACh) release. In the present study, we investigated the role of dopamine in the developmental regulation of prefrontal cortical ACh release and the expression of nicotinic and muscarinic receptors in pre- and post-pubertal rats with neonatal ibotenic acid-induced lesions of the ventral hippocampus (NVH). In vivo microdialysis in the PFC revealed that systemic injections of the D(1)-like receptor agonist (+/-)-6-chloro-7,8-dihydroxy-1-phenyl2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF 81297) (2.5 and 5.0 mg/kg i.p.) caused significantly higher ACh release in post-pubertal NVH-lesioned animals (250 and 300% baseline for 2.5 and 5.0 mg/kg, respectively) compared with post-pubertal shams (150 and 220% baseline for 2.5 and 5.0 mg/kg, respectively). Most interestingly, while prefrontal cortical perfusion of SKF 81297 (100 and 250 microM) had no significant effect on ACh release in post-pubertal sham-operated animals, it significantly stimulated ACh release to approximately 250% baseline at both doses in post-pubertal NVH-lesioned animals. Receptor autoradiography demonstrated a significant and selective increase in M(1)-like receptor binding sites in the infralimbic area of the PFC in the post-pubertal NVH-lesioned animals. For all experiments, significant differences between sham and NVH-lesioned animals were observed only in post-pubertal rats. These results suggest a developmentally specific reorganization of the prefrontal cortical cholinergic system involving D(1)-like receptors in the NVH model.

Lateralized Attentional Functions of Cortical Cholinergic Inputs.

The integrity of the cortical cholinergic input system is necessary for attention performance. This experiment tested hypotheses concerning the lateralized contributions of cortical cholinergic inputs to attention performance by assessing the effects of unilateral lesions of basal forebrain cholinergic neurons on sustained attention performance. Loss of right-hemispheric cortical cholinergic inputs impaired the rats' ability to detect signals but did not affect nonsignal trial performance. Conversely, loss of left-hemispheric cortical cholinergic inputs increased the number of false alarms in nonsignal trials. These data correspond with hypotheses about the mediation of detection processes primarily by right-hemispheric circuits and executive aspects of attention performance by left-hemispheric systems. Cortical cholinergic inputs represent a major component of the brain's lateralized attention systems.

Visceral Afferent Bias on Cortical Processing: Role of Adrenergic Afferents to the Basal Forebrain Cholinergic System.

Intraperitoneal epinephrine enhances the cerebral auditory evoked potential (AEP), an effect that is dependent on the basal forebrain cortical cholinergic system. The present study examined the hypothesis that ascending noradrenergic projections from brainstem autonomic substrates to the basal forebrain cholinergic system represent an essential component of the ascending pathway mediating this effect of epinephrine. Epinephrine again enhanced the AEP in rats, and this effect was attenuated by infusion of the selective alpha1 adrenergic antagonist terazosin into the basal forebrain. Moreover, infusions of the selective alpha1 adrenergic agonist phenylephrine into the basal forebrain mimicked the priming effects of epinephrine. Results support the hypothesis that noradrenergic afferents to the basal forebrain cholinergic system represent a component of an ascending visceral afferent system.