Modulatory action of cholinergic drugs on N-methyl-D-aspartate response in dissociated rat nucleus basalis of Meynert neurons.

The effect of cholinergic drugs on N-methyl-D-aspartate (NMDA)-activated responses in neurons dissociated freshly from the nucleus basalis of Meynert (nBM) of immature and mature rats were investigated with the whole-cell patch-clamp technique. The NMDA (10(-4) M)-evoked inward current (INMDA) consisted of transient peak and successive steady-state components. In mature neurons, the peak component was suppressed by pretreatment with acetylcholine (ACh, 10(-12)-10(-5) M) but facilitated by higher concentrations (greater than 10(-5) M). Regardless of the concentration, ACh had no effect on INMDA of immature neurons. The results suggest that ACh behaves as either inhibitory or excitatory modulator of glutaminergic transmission in nBM neurons of adult mammals depending on ACh concentration.     

Physiologic effects of nucleus basalis magnocellularis stimulation on rat barrel cortex neurons

Cholinergic neurons in the nucleus basalis magnocellularis (NBM) project to the cerebral cortex and are thought to play an important role in learning and memory, and other cognitive functions. In the present study, we examined the effects of NBM stimulation on the response properties of individual cortical neurons in layer V of the rat somatosensory cortex. Seventy-three neurons were studied before and after a brief electrical stimulation of NBM. Transient changes in spontaneous activity were observed in 60% of the cells, and in most cases this background activity decreased. Recordings lasting more than 1 h stimulation were obtained from 56 cells. Because some NBM stimulation-induced effects lasted several hours, neurons were evaluated in two groups, NBM1 and NBM2. NBM1 neurons were those exposed to either the first NBM stimulation of the day or an NBM restimulation following a more than 5 h stimulation-free period. Neurons exposed to NBM restimulation following a stimulation free interval of less than 5 h were classified as NBM2. Sixty-nine percent of the 32 NBM1 neurons displayed marked decreases in spontaneous activity and/or increases in the response evoked by deflecting a contralateral facial vibrissa. NBM1 stimulation caused some units to respond to previously minimally effective whisker stimuli. Stimulation effects often lasted several hours. By contrast, long-lasting changes were observed in only 25% of the 24 NBM2 neurons, and the only consistent effect was on spontaneous, not stimulus-evoked, activity. Systemic injection of atropine blocked NBM stimulation-induced changes in spontaneous and stimulus-evoked activities. Control neurons, studied without NBM stimulation, failed to display consistent alterations in their response properties during the course of 1 h or more. Results demonstrate that NBM activation produces long-lasting, cholinergically mediated alterations in the response properties of somatosensory cortical neurons. Effects were complex, being influenced by factors such as the time interval between successive stimulations during an experiment. The complexity of these NBM mediated effects should be considered when designing therapies for neurodegenerative disorders characterized by loss of NBM neurons.     

Serotonergic input to cholinergic neurons in the substantia innominata and nucleus basalis magnocellularis in the rat.

The aim of the present study was to determine, at the light microscopic level, whether the serotonergic fibers originating from the dorsal raphe nucleus (B7), median raphe nucleus (B8) and ventral tegmentum (B9) make putative synaptic contacts with cholinergic neurons of the nucleus basalis magnocellularis and substantia innominata. For this purpose, we utilized: (i) the anterograde transport of Phaseolus vulgaris leucoagglutinin combined with choline acetyltransferase immunohistochemistry; (ii) choline acetyltransferase/tryptophan hydroxylase double immunohistochemistry; and (iii) the FluoroGold retrograde tracer technique combined with tryptophan hydroxylase immunohistochemistry. Following iontophoretic injections of Phaseolus vulgaris leucoagglutinin in the dorsal raphe nucleus, labeling was observed primarily in the ventral aspects of the nucleus basalis magnocellularis and in the intermediate region of the substantia innominata. When Phaseolus vulgaris leucoagglutinin was combined with choline acetyltransferase immunohistochemistry, a close association between the Phaseolus vulgaris leucoagglutinin-positive fibers and cholinergic neurons was observed, even though the majority of the Phaseolus vulgaris leucoagglutinin-immunoreactive terminals seemed to establish contact with non-cholinergic elements. Following Phaseolus vulgaris leucoagglutinin injection in the median raphe nucleus, very few labeled fibers with no evident close contact with nucleus basalis magnocellularis and substantia innominata cholinergic neurons were observed. After tryptophan hydroxylase/choline acetyltransferase double immunohistochemistry, a plexus of serotonergic (tryptophan hydroxylase-positive) fibers in the vicinity of choline acetyltransferase-immunoreactive neurons of the substantia innominata and nucleus basalis magnocellularis was observed, and some serotonergic terminals have been shown to come into very close contact with the cholinergic cells. Most of the tryptophan hydroxylase-immunoreactive terminals seem to establish contacts with non-cholinergic cells. Following FluoroGold injection in the nucleus basalis magnocellularis and substantia innominata, the majority of retrogradely labeled neurons was observed mainly in the ventromedial cell group of the dorsal raphe nucleus. In this area, a minority of the FluoroGold-positive neurons was tryptophan hydroxylase immunoreactive. These findings show that serotonergic terminals, identified in very close association with the cholinergic neurons in the substantia innominata and nucleus basalis magnocellularis, derive primarily from the B7 serotonergic cell group of the dorsal raphe nucleus, and provide the neuroanatomical evidence for a direct functional interaction between these two neurotransmitter systems in the basal forebrain.     

Lamellar bodies are markers of cholinergic neurons in ferret nucleus basalis

Summary Lamellar bodies are composed of stacks of closely-packed, ribosome-free cisterns which are in continuity with the rough endoplasmic reticulum. In the ferret nucleus basalis stained for choline acetyltransferase it was shown, by correlating light with electron microscopy, that only the cholinergic cells there possess lamellar bodies. The significance of lamellar bodies in the cholinergic neurons of the nucleus basalis is not known, but these structures may reflect a peculiar aspect of the functioning of the cholinergic cells which will need to be investigated further.     

Nicotinic cholinergic activation of magnocellular neurons of the hypothalamic paraventricular nucleus

The aim of the present work was to determine whether paraventricular neurons possess functional acetylcholine nicotinic receptors. Using infrared videomicroscopy and differential interference contrast optics, we performed whole-cell recordings in hypothalamic slices containing the paraventricular nucleus. Acetylcholine, locally applied by pressure microejection in the presence of the muscarinic antagonist atropine, evoked a rapidly rising inward current in paraventricular magnocellular endocrine neurons. This current persisted in the presence of blockers of synaptic transmission. It could be reversibly suppressed by nanomolar concentrations of methyllycaconitine, a selective antagonist of alpha 7-containing nicotinic receptors, but was insensitive to micromolar concentrations of dihydro-beta-erythroidine, an antagonist acting preferentially on non-alpha 7 nicotinic receptors. In addition, the effect of acetylcholine could be mimicked by exo-2-(2-pyridyl)-7-azabicyclo[2.2.1]heptane, a recently synthesized nicotinic agonist specific for alpha 7 receptors. Acetylcholine also desensitized paraventricular nicotinic receptors. Desensitization was pronounced and recovery from desensitization was rapid, consistent with the notion that paraventricular nicotinic receptors contain the alpha 7 subunit. Nicotinic currents could not be evoked in paraventricular parvocellular neurons, suggesting that these neurons are devoid of functional nicotinic receptors. The electrophysiological data were corroborated by light microscopic autoradiography, showing that [(125)I]alpha-bungarotoxin binding sites are present in all the magnocellular divisions of the paraventricular nucleus but are undetectable in other areas of this nucleus. Immunohistochemistry, performed using antibodies directed against vasopressin and oxytocin, indicated that responsiveness to nicotinic agonists was a property of vasopressin as well as of oxytocin magnocellular endocrine neurons, in both the paraventricular and the supraoptic nucleus. We conclude that nicotinic agonists can influence the magnocellular neurosecretory system by directly increasing the excitability of magnocellular neurons. By contrast, they are probably without direct effects on paraventricular parvocellular neurons.     

Atrophy of cholinergic neurons within the rat nucleus basalis magnocellularis following intracortical AF64A infusion

The rat nucleus basalis magnocellularis (nBM) was morphometrically analyzed following multiple intracortical AF64A infusions. At 3 weeks post-infusion, brains were histochemically double-stained for acetyl-cholinesterase and Nissl substance following diisopropylfluorophosphate pretreatment. Intracortical AF64A induced significant atrophy, but not degeneration, of nucleus basalis cholinergic cell bodies. These results suggest that retrograde cellular atrophy is associated with inhibition of presynaptic high-affinity choline transport on cortical terminals of nBM cholinergic neurons.     

Loss of cholinergic neurons in the nucleus basalis induces neocortical electroencephalographic and passive avoidance deficits.

The present experiments were designed to examine the hypothesis that the degeneration of cholinergic nucleus basalis is related to the cognitive and neurophysiological deficits found in old age. Aged (26 months) rats were impaired both in the acquisition of spatial (water-maze) task and retention of passive avoidance task. During aging, neocortical electroencephalographic fast activity was decreased and high-voltage spindles increased. Loss of choline acetyltransferase-positive neurons correlated with the high-voltage spindle incidence and passive avoidance retention deficit. Unilateral ibotenate nucleus basalis lesioning decreased choline acetyltransferase activity in the cortex and produced a large nonspecific subcortical cell loss in young rats. Ibotenate-lesioned rats were impaired in spatial learning and passive avoidance retention in young rats. Quisqualic acid produced a greater decrease in cortical choline acetyltransferase activity and smaller nonspecific subcortical cell loss than ibotenate lesioning. Spatial learning was not impaired, but passive avoidance performance was disrupted. Slow waves and high-voltage spindles were increased and beta activity decreased on the side of either quisqualate or ibotenate nucleus basalis lesioning. These results demonstrate that age-related neurophysiological and cognitive deficits result partially from the loss of cholinergic neurons in the nucleus basalis and that quisqualic acid nucleus basalis-lesioning in young rats may be used as a pharmacological model of the age-related cholinergic neuron loss.     

Selective immunolesioning of cholinergic neurons in nucleus basalis magnocellularis impairs prepulse inhibition of acoustic startle.

Information processing and attentional abnormalities are prominent in neuropsychiatric disorders. Since the cholinergic neurons located in the nucleus basalis magnocellularis have been shown to be involved in attentional performance and information processing, recent efforts to analyze the significance of the basal forebrain in the context of schizophrenia have focused on this nucleus and its projections to the cerebral cortex. We report here that bilateral selective immunolesioning of the cholinergic neurons in the nucleus basalis magnocellularis is followed by significant deficits in sensorimotor gating measured by prepulse inhibition of the startle reflex in adult rats. This behavioral approach is used in both humans and rodents and has been proposed as a valuable model contributing to the understanding of the neurobiological substrates of schizophrenia. The disruption of prepulse inhibition persisted over repeated testing. The selective lesions were induced by bilateral intraparenchymal infusions of 192 IgG saporin at a concentration having minimal diffusion into adjacent nuclei of the basal forebrain. The infusions were followed by extensive loss of choline acetyltransferase-immunopositive neurons. Our results show that the cholinergic neurons of the nucleus basalis magnocellularis represent a critical station of the startle gating circuitry and suggest that dysfunction of these neurons may result in impaired sensorimotor gating characteristic of schizophrenia.     

Cortically projecting nucleus basalis neurons in rat are physiologically heterogeneous

The localization of serotonin and non-serotonin-containing cell bodies in the interpeduncular nucleus of the rat that project to the hippocampal formation was studied using the technique of retrograde tracing of Granular Blue and immunohistochemistry on the same sections. The results indicate that the caudal magnocellular subnucleus (pars dorsalis magnocellularis) and, to a lesser extent, the caudal part of the lateral subnucleus (par lateralis) of the interpeduncular nucleus send serotonin as well as non-serotonin fibers to the ventral hippocampus.     

Met-enkephalin induces fast synaptic plasticity of magnocellular neurons in the rat supraoptic nucleus.

A morphometric-ultrastructural study was made of the supraoptic nucleus of rats of both sexes following central administration of met-enkephalin. Ten minutes after met-enkephalin treatment the number of axo-somatic synapses was significantly increased. This effect was more pronounced in female rats than in males and could be prevented by preceding administration of naloxone. Animals that received naloxone followed by met-enkephalin showed a dilation of the rough endoplasmic reticulum into a vesicular shape. Our results provide preliminary evidence for a fast remodeling of synaptic input to magnocellular hypothalamic neurons. It is likely that the known inhibitory action of opioids on the hypothalamo-neurohypophysial system is partly mediated by this plasticity.     

Effect of hypertonic saline on rat hypothalamic paraventricular nucleus magnocellular neurons in vitro

The effect of hypertonic saline on rat hypothalamic paraventricular nucleus (PVN) magnocellular neurons was examined using a whole-cell patch-clamp technique. Under a current-clamp, 58/68 of magnocellular neurons were depolarized by hypertonic stimulation. Under a voltage-clamp, hypertonic saline produced an inward current via increased non-selective cationic conductance and shifting of the reversal potential to more positive values. Furthermore, hypertonic saline even without a change in osmolality increased spontaneous excitatory postsynaptic currents (sEPSCs). A bath application of CNQX almost completely blocked EPSCs. Extracellular application of gadolinium blocked the hypertonic saline- and mannitol-induced response. These results suggest that PVN magnocellular neurons are responsive to osmolality and Na+ concentrations. Hypertonic saline excited PVN magnocellular neurons via osmo-reception, Na+ -detection, and excitatory glutamatergic synaptic input.     

Electrophysiological properties of cholinergic and noncholinergic neurons in the ventral pallidal region of the nucleus basalis in rat brain slices

The ventral pallidum is a major source of output for ventral corticobasal ganglia circuits that function in translating motivationally relevant stimuli into adaptive behavioral responses. In this study, whole cell patch-clamp recordings were made from ventral pallidal neurons in brain slices from 6- to 18-day-old rats. Intracellular filling with biocytin was used to correlate the electrophysiological and morphological properties of cholinergic and noncholinergic neurons identified by choline acetyltransferase immunohistochemistry. Most cholinergic neurons had a large whole cell conductance and exhibited marked fast (i.e., anomalous) inward rectification. These cells typically did not fire spontaneously, had a hyperpolarized resting membrane potential, and also exhibited a prominent spike afterhyperpolarization (AHP) and strong spike accommodation. Noncholinergic neurons had a smaller whole cell conductance, and the majority of these cells exhibited marked time-dependent inward rectification that was due to an h-current. This current activated slowly over several hundred milliseconds at potentials more negative than -80 mV. Noncholinergic neurons fired tonically in regular or intermittent patterns, and two-thirds of the cells fired spontaneously. Depolarizing current injection in current clamp did not cause spike accommodation but markedly increased the firing frequency and in some cells also altered the pattern of firing. Spontaneous tetrodotoxin-sensitive GABA(A)-mediated inhibitory postsynaptic currents (IPSCs) were frequently recorded in noncholinergic neurons. These results show that cholinergic pallidal neurons have similar properties to magnocellular cholinergic neurons in other parts of the forebrain, except that they exhibit strong spike accommodation. Noncholinergic ventral pallidal neurons have large h-currents that could have a physiological role in determining the rate or pattern of firing of these cells.     

Acetylcholine receptors in dissociated nucleus basalis of Meynert neurons of the rat

Electrical and pharmacological properties of acetylcholine (ACh)-induced currents in neurons dissociated from the nucleus basalis of Meynert (nBM) of immature (2-week-old) rats were investigated with the whole-cell mode of the patch-clamp technique. At a holding potential (V_H) of −50 mV, ACh (10⁻⁴M) evoked a transient inward current mimicked by nicotine (I_nACh), followed by a sustained outward current mimicked by carbamylcholine (I_mACh). The K_D values were 1.2 × 10⁻⁴ M for I_nACh) and 8.7 × 10⁻⁷ M for I_mACh. The reversal potenial of I_mACh was close to E_K. The I_mACh was determined to be elicited via the M₂ muscarinic receptor, based on the differences in sensitivity to muscarinic antagonists such as pirenzepine and AF-DX-116.     

Nerve growth factor effects on cholinergic neurons of neostriatum and nucleus accumbens in the adult rat

Following intraventricular nerve growth factor infusion in adult rats, the choline acetyltransferase immunostaining of the neuropil and neuronal cell bodies of the neostriatum (caudate-putamen) and nucleus accumbens was more intense on the side of the infusion. Furthermore, the average cross-sectional size (micron2) of the cholinergic somata was increased by about 40 and 20% in the striatum and accumbens, respectively. This unilateral response could be elicited in intact rats as well as in rats receiving a prior aspirative transection of the fimbria-fornix. The reported lack of (low-affinity) nerve growth factor receptor immunostaining in these neurons suggests that the nerve growth factor effects are most likely transduced by high-affinity receptors. The ability of these apparently undamaged cholinergic interneurons to respond to exogenous nerve growth factor with an increase in choline acetyltransferase content and cell body size suggests that they are benefiting from a less-than-maximal support by endogenous nerve growth factor in the normal young adult rat.     

Intrinsic excitability of cholinergic neurons in the rat parabigeminal nucleus

Cholinergic neurons in the parabigeminal nucleus of the rat midbrain were studied in an acute slice preparation. Spontaneous, regular action potentials were observed both with cell-attached patch recordings as well as with whole cell current-clamp recordings. The spontaneous activity of parabigeminal nucleus (PBN) neurons was not due to synaptic input as it persisted in the presence of the pan-ionotropic excitatory neurotransmitter receptor blocker, kynurenic acid, and the cholinergic blockers dihydro-beta-erythroidine (DHbetaE) and atropine. This result suggests the existence of intrinsic currents that enable spontaneous activity. In voltage-clamp recordings, I(H) and I(A) currents were observed in most PBN neurons. I(A) had voltage-dependent features that would permit it to contribute to spontaneous firing. In contrast, I(H) was significantly activated at membrane potentials lower than the trough of the spike afterhyperpolarization, suggesting that I(H) does not contribute to spontaneous firing of PBN neurons. Consistent with this interpretation, application of 25 microM ZD-7288, which blocked I(H), did not affect the rate of spontaneous firing in PBN neurons. Counterparts to I(A) and I(H) were observed in current-clamp recordings: I(A) was reflected as a slow voltage ramp observed between action potentials and on release from hyperpolarization, and I(H) was reflected as a depolarizing sag often accompanied by rebound spikes in response to hyperpolarizing current injections. In response to depolarizing current injections, PBN neurons fired at high frequencies, with relatively little accommodation. Ultimately, the spontaneous activity in PBN neurons could be used to modulate cholinergic drive in the superior colliculus in either positive or negative directions.     

Rac1b increases with progressive tau pathology within cholinergic nucleus basalis neurons in Alzheimer's disease

Cholinergic basal forebrain (CBF) nucleus basalis (NB) neurons display neurofibrillary tangles (NFTs) during Alzheimer's disease (AD) progression, yet the mechanisms underlying this selective vulnerability are currently unclear. Rac1, a member of the Rho family of GTPases, may interact with the proapoptotic pan-neurotrophin receptor p75(NTR) to induce neuronal cytoskeletal abnormalities in AD NB neurons. Herein, we examined the expression of Rac1b, a constitutively active splice variant of Rac1, in NB cholinergic neurons during AD progression. CBF tissues harvested from people who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment, or AD were immunolabeled for both p75(NTR) and Rac1b. Rac1b appeared as cytoplasmic diffuse granules, loosely aggregated filaments, or compact spheres in p75(NTR)-positive NB neurons. Although Rac1b colocalized with tau cytoskeletal markers, the percentage of p75(NTR)-immunoreactive neurons expressing Rac1b was significantly increased only in AD compared with both mild cognitive impairment and NCI. Furthermore, single-cell gene expression profiling with custom-designed microarrays showed down-regulation of caveolin 2, GNB4, and lipase A in AD Rac1b-positive/p75(NTR)-labeled NB neurons compared with Rac1b-negative/p75(NTR)-positive perikarya in NCI. These proteins are involved in Rac1 pathway/cell cycle progression and lipid metabolism. These data suggest that Rac1b expression acts as a modulator or transducer of various signaling pathways that lead to NFT formation and membrane dysfunction in a subgroup of CBF NB neurons in AD.     

Dye-coupled magnocellular peptidergic neurons of the rat paraventricular nucleus show homotypic immunoreactivity

Magnocellular neurons in rat hypothalamic slices are known to exhibit dye coupling: the transfer of the fluorescent dye, Lucifer Yellow, from an intracellularly-injected neuron to one or more nearby neurons. The question of the hormonal identity of coupled cells and the possibility of dye coupling as an artefact led us to determine the immunoreactivity of dye-coupled magnocellular neurons in the paraventricular nucleus of the rat hypothalamus using antisera to oxytocin- and vasopressin-associated neurophysins. In 23 pairs, one triplet, and one quadruplet, immunoreactivity to one or the other antiserum was always exclusive, and dye coupling was always homotypic, that is, coupled neurons in each instance were reactive to the same antiserum. The quadruplet, triplet and 17 pairs were immunoreactive to vasopressin-associated neurophysin, and oxytoxin-associated neurophysin immunoreactivity was observed in the remaining pairs. Immunoreactivity to each antiserum was found for somasomatic and non somasomatic modes of coupling and for coupled neurons in the three magnocellular areas of the nucleus. A relationship between mode of coupling and hormone content was not detected. The data support the hypothesis that coupling is a real, functionally significant mechanism for coordinating neuronal activity in this nucleus, particularly under conditions of high hormone demand. They do not support the idea that coupling is artefact. The possibility of a relationship between hormone content and mode of coupling, and the projection pathway(s) of the coupled neurons of each type require further study.     

N-methyl-D-aspartate receptors on neurons that synthesize nitric oxide in rat nucleus tractus solitarii

The aim of this study was to determine whether neuronal nitric oxide synthase and N-methyl-D-aspartate receptors are co-localized in the rat nucleus tractus solitarii. Such co-localization would support the hypothesis that nitric oxide participates in nucleus tractus solitarii-mediated functions, such as cardiovascular regulation, by a link to N-methyl-D-aspartate receptors. We used double fluorescent immunohistochemistry using antibodies against neuronal nitric oxide synthase and N-methyl-D-aspartate receptor subunit 1, the fundamental subunit for functional N-methyl-D-aspartate receptors. Labeled brainstem sections were examined with confocal laser scanning microscopy. Most of the N-methyl-D-aspartate receptor subunit 1 immunoreactivity was in cell bodies and proximal dendrites of the numerous labeled cells in the brainstem. High levels of N-methyl-D-aspartate receptor subunit 1 immunoreactivity were present in the dorsal motor nucleus of vagus, hypoglossal nucleus and nucleus ambiguus. All subnuclei of the nucleus tractus solitarii contained moderate levels of N-methyl-D-aspartate receptor subunit 1 immunoreactivity. The distribution of neuronal nitric oxide synthase immunoreactivity in the nucleus tractus solitarii was similar to that described in earlier reports. Superimposition of images revealed that almost all neuronal nitric oxide synthase immunoreactive neurons in the nucleus tractus solitarii contained N-methyl-D-aspartate receptor subunit 1 immunoreactivity, but a lesser portion of N-methyl-D-aspartate receptor subunit 1-immunoreactive cells contained neuronal nitric oxide synthase immunoreactivity. Although all nucleus tractus solitarii subnuclei contained double-labeled neurons, the central subnucleus exhibited the highest density of double-labeled neurons.Co-localization of neuronal nitric oxide synthase and N-methyl-D-aspartate receptor subunit 1 in the nucleus tractus solitarii provides anatomical support for the hypothesis that N-methyl-D-aspartate receptor activation can affect nucleus tractus solitarii-controlled functions via actions on neurons that synthesize nitric oxide.     

Rivastigmine antagonizes deficits in prepulse inhibition induced by selective immunolesioning of cholinergic neurons in nucleus basalis magnocellularis

Impairments of cortical cholinergic inputs from the nucleus basalis magnocellularis fundamentally alter information processing and attentional function, thereby advancing the severity of psychopathology in major neuropsychiatric disorders. It was previously shown in adult rats that bilateral 192 IgG saporin-induced selective immunolesioning of the cholinergic neurons in the nucleus basalis produces pronounced and long-lasting deficits in sensorimotor gating measured by prepulse inhibition of the startle reflex. This behavioral paradigm is considered a valid model of sensorimotor gating deficits in the psychotic spectrum and efforts to analyze the significance of the cholinergic basal forebrain in this context are of great interest. In the present study the predictive value of the selective cholinergic immunolesioning model was tested by examining the ability of the cholinesterase inhibitor rivastigmine to restore prepulse inhibition in immunolesioned rats. We report here a pronounced restoring effect of acute (0.75 or 1.5 mg/kg s.c.) as well as repeated (0.75 mg/kg s.c. b.i.d., for 10 days) treatment with rivastigmine in this model of disrupted prepulse inhibition. Intra-nucleus basalis magnocellularis infusions of 192 IgG saporin resulted in extensive loss of basal-cortical cholinergic neurons as shown by the marked decrease in basal telencephalic choline acetyltransferase immunopositive neurons and cortical choline acetyltransferase activity. In this condition, rivastigmine was found to significantly increase cortical acetylcholine extracellular levels in lesioned animals measured by in vivo microdialysis. Taken together, our results strengthen the proposal that the nucleus basalis represents a critical station of the startle gating circuitry. In addition, our findings strongly indicate that even after dramatic decrease of cholinergic neurons, inhibition of acetylcholinesterase restores the cholinergic synaptic function to a point approaching normalization of experimentally induced psychopathology.     

The nucleus basalis magnocellularis: The origin of a cholinergic projection to the neocortex of the rat

The cells of origin of a neocortical cholinergic afferent projection have been identified by anterograde and retrograde methods in the rat. Horseradish peroxidase injected into neocortex labelled large, acetylcholinesterase-rich neurons in the ventromedial extremity of the globus pallidus. This same group of neurons underwent retrograde degeneration following cortical ablations. The region in which cell depletion occurred also showed significant decreases in the activities of choline acetyltransferase and acetylcholinesterase. Discrete electrolytic and kainic acid lesions restricted to the medial part of the globus pallidus each resulted in significant depletions of neocortical choline acetyltransferase and acetylcholinesterase. Hemitransections caudal to this cell group did not result in such depletions. Taken together these observations suggest that the acetylcholinesterase-rich neurons lying in the ventromedial extremity of the globus pallidus, as mapped in this study, constitute the origin of a major subcortical cholinergic projection to the neocortex. The utility of acetylcholinesterase histochemistry in animals pretreated with di-isopropylphosphorofluoridate in identifying cholinergic neurons is discussed in the light of this example; specifically, it is proposed that high acetylcholinesterase activity 4–8 h after this pretreatment is a necessary, but not sufficient, criterion for the identification of cholinergic perikarya.The neurons in question appear to be homologous to the nucleus basalis of the substantia innominata of primates, and are thus termed ‘nucleus basalis magnocellularis’ in the rat. No evidence was obtained to support the hypothesis that nucleus of the diagonal band projects to neocortex. However, striking similarities in size and acetylcholinesterase activity were observed among the putative cholinergic perikarya of the nucleus basalis magnocellularis, the nucleus of the diagonal band, and the medial septal nucleus.Kainic acid lesions of the neocortex produced uniform and complete destruction of neuronal perikarya. These lesions decreased neocortical glutamic acid decar?ylase activity, suggesting that there are GABAergic perikarya in the neocortex. However, the same lesions did not affect neocortical choline acetyltransferase. This observation suggests that there are no cholinergic perikarya in the neocortex, a conclusion that is consistent with the absence of intensely acetylcholinesterase-reactive neurons in the neocortex.