Papers by Lynda Mainville
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 2000
The brainstem contains the neural systems that are necessary for the generation of the state of p... more The brainstem contains the neural systems that are necessary for the generation of the state of paradoxical sleep (PS) and accompanying muscle atonia. Important for its initiation are the pontomesencephalic cholinergic neurons that project into the pontomedullary reticular formation and that we have recently shown increase c-Fos expression as a reflection of neural activity in association with PS rebound after deprivation in rats (Maloney et al. , 1999). As a continuation, we examined in the present study c-Fos expression in the pontomedullary reticular and raphe neurons, including importantly GABAergic neurons [immunostained for glutamic acid decarboxylase (GAD)] and serotonergic neurons [immunostained for serotonin (Ser)]. Numbers of single-labeled c-Fos+ neurons were significantly increased with PS rebound only in the pars oralis of the pontine reticular nuclei (PnO), where numbers of GAD+/c-Fos+ neurons were conversely significantly decreased. c-Fos+ neurons were positively corr...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 1999
Multiple lines of evidence indicate that neurons within the pontomesencephalic tegmentum are crit... more Multiple lines of evidence indicate that neurons within the pontomesencephalic tegmentum are critically involved in the generation of paradoxical sleep (PS). From single-unit recording studies, evidence suggests that unidentified but "possibly" cholinergic tegmental neurons discharge at higher rates during PS than during slow wave sleep or even waking and would thus play an active role, whereas "presumed" monoaminergic neurons cease firing during PS and would thus play a permissive role in PS generation. In the present study performed on rats, c-Fos immunostaining was used as a reflection of neuronal activity and combined with immunostaining for choline acetyltransferase (ChAT), serotonin (Ser), tyrosine hydroxylase (TH), or glutamic acid decarboxylase (GAD) for immunohistochemical identification of active neurons during PS recovery ( approximately 28% of recording time) as compared with PS deprivation (0%) and PS control (approximately 15%) conditions. With PS r...
BMC neuroscience, 2007
The basal forebrain (BF) cholinergic neurons play an important role in cortical activation and ar... more The basal forebrain (BF) cholinergic neurons play an important role in cortical activation and arousal and are active in association with cortical activation of waking and inactive in association with cortical slow wave activity of sleep. In view of findings that GABAA receptors (Rs) and inhibitory transmission undergo dynamic changes as a function of prior activity, we investigated whether the GABAARs on cholinergic cells might undergo such changes as a function of their prior activity during waking vs. sleep. In the brains of rats under sleep control (SC), sleep deprivation (SD) or sleep recovery (SR) conditions in the 3 hours prior to sacrifice, we examined immunofluorescent staining for beta2-3 subunit GABAARs on choline acetyltransferase (ChAT) immunopositive (+) cells in the magnocellular BF. In sections also stained for c-Fos, beta2-3 GABAARs were present on ChAT+ neurons which expressed c-Fos in the SD group alone and were variable or undetectable on other ChAT+ cells across...
Neuroscience, 2001
Basal forebrain neurons play important parts in processes of cortical activation and memory that ... more Basal forebrain neurons play important parts in processes of cortical activation and memory that have been attributed to the cortically projecting, cholinergic neurons. Yet, non-cholinergic neurons also project to the cerebral cortex and also appear to participate in processes of cortical modulation and plasticity. GABAergic neurons compose a portion of the cortically projecting cell group, but do not fully account for the non-cholinergic cell contingent. In the present study in the rat, we investigated whether the non-cholinergic, non-GABAergic cell component might be composed of glutamatergic neurons. We examined afferents to the entorhinal cortex, which is known to be modulated by basal forebrain neurons and to be critically involved in memory. Dual immunofluorescent staining was performed for cholera toxin, as retrograde tracer, and phosphate-activated glutaminase, the synthetic enzyme for the neurotransmitter pool of glutamate. The retrogradely labeled cells were distributed across the basal forebrain through the medial septum, diagonal band, magnocellular preoptic area and substantia innominata. The major proportion (approximately 80%) of the retrogradely labeled cells was found to be immunopositive for phosphate-activated glutaminase. Equal minor proportions (approximately 40%) were immunopositive for choline acetyltransferase and glutamic acid decarboxylase. In other material dual-immunostained for neurotransmitter enzymes, approximately 95% of choline acetyltransferase- and approximately 60% of glutamic acid decarboxylase-immunopositive neurons were also immunopositive for phosphate-activated glutaminase. From these results it appears that a significant proportion of these cell groups, including their cortically projecting contingents, could synthesize glutamate together with acetylcholine or GABA as neurotransmitters and another proportion of cells could synthesize glutamate alone. Accordingly, as either co-transmitter or primary transmitter within basalocortical afferents, glutamate could have the capacity to modulate the entorhinal cortex and promote its role in memory.
Journal of Neuroscience, 2014
Distributed within the laterodorsal tegmental and pedunculopontine tegmental nuclei (LDT and PPT)... more Distributed within the laterodorsal tegmental and pedunculopontine tegmental nuclei (LDT and PPT), cholinergic neurons in the pontomesencephalic tegmentum have long been thought to play a critical role in stimulating cortical activation during waking (W) and paradoxical sleep (PS, also called REM sleep), yet also in promoting PS with muscle atonia. However, the discharge profile and thus precise roles of the cholinergic neurons have remained uncertain because they lie intermingled with GABAergic and glutamatergic neurons, which might also assume these roles. By applying juxtacellular recording and labeling in naturally sleeping-waking, head-fixed rats, we investigated the discharge profiles of histochemically identified cholinergic, GABAergic, and glutamatergic neurons in the LDT, SubLDT, and adjoining medial part of the PPT (MPPT) in relation to sleep-wake states, cortical activity, and muscle tone. We found that all cholinergic neurons were maximally active during W and PS in positive correlation with fast (␥) cortical activity, as "W/PS-max active neurons." Like cholinergic neurons, many GABAergic and glutamatergic neurons were also "W/PS-max active." Other GABAergic and glutamatergic neurons were "PS-max active," being minimally active during W and maximally active during PS in negative correlation with muscle tone. Conversely, some glutamatergic neurons were "W-max active," being maximally active during W and minimally active during PS in positive correlation with muscle tone. Through different discharge profiles, the cholinergic, GABAergic, and glutamatergic neurons of the LDT, SubLDT, and MPPT thus appear to play distinct roles in promoting W and PS with cortical activation, PS with muscle atonia, or W with muscle tone.
Neuroscience, 2004
The basal forebrain (BF) contains cholinergic neurons that stimulate cortical activation during w... more The basal forebrain (BF) contains cholinergic neurons that stimulate cortical activation during waking. In addition, both the BF and adjacent preoptic area (POA) contain neurons that promote sleep. We examined c-Fos expression in cholinergic and GABAergic neurons in the BF and POA to determine whether they are differentially active following sleep deprivation versus recovery and whether the GABAergic neurons are
Neuroscience, 1994
As part of a larger study concerning the role of neurons in the medial medullary reticular format... more As part of a larger study concerning the role of neurons in the medial medullary reticular formation in sleep-wake states, the distribution and projections of cholinergic, GABAergic and serotonergic neurons were studied within the lower brainstem of the cat. Cells were plotted with the aid of an image analysis system through the medullary reticular formation and raphe in adjacent sections immunostained for choline acetyltransferase, glutamic acid decarboxylase and serotonin. Immunostained fibres and varicosities were examined and quantified by microdensitometry in regions of the medulla, pons and upper spinal cord in normal and quisqualate-injected animals to assess the loss of local and distant projections following cytotoxic destruction of neurons in the medial medullary reticular formation. Choline acetyltransferase-immunoreactive neurons are unevenly and sparsely distributed, though none the less in significant numbers (estimated at approximately 9080 in total), through the medial medullary reticular formation, and are present in all tegmental fields, including the gigantocellular (approximately 3700) and magnocellular (approximately 1760) rostrally and the ventral (approximately 3240) and paramedian (approximately 380) caudally, and are absent in the midline raphe. Glutamic acid decarboxylase-immunoreactive neurons are more evenly and densely distributed in large numbers (estimated at approximately 18,720) through the medial medullary reticular formation, being present in the gigantocellular (approximately 5960), magnocellular (approximately 8260), ventral (approximately 2280) and paramedian (approximately 2220) tegmental fields, and are also numerous within the raphe magnus and pallidus-obscurus nuclei (approximately 3880). Serotonin-immunoreactive cells are sparse in the medial medullary reticular formation (estimated to total approximately 1540), where they are mainly located in the magnocellular tegmental field (approximately 1340), and are concentrated in larger numbers within the raphe nuclei (approximately 8060). Cholinergic varicose fibres were moderately densely distributed through the medial medullary reticular formation, as well as through more distant lateral, rostral and caudal brainstem and upper spinal regions. After cytotoxic lesions focussed in the gigantocellular and magnocellular tegmental fields, a loss of approximately 55% of the cholinergic neurons in the medial medullary reticular formation was associated with a minor decrease (approximately 35% in optical density measures) of local cholinergic fibres. Small and variable reductions in varicose fibres (and their optical density measures) were detected in distant structures (including the pontine lateral, gigantocellular and subcoerular tegmental fields and the caudal spinal trigeminal nucleus), that were none the less correlated with the number of intact medial medullary cholinergic cells, suggesting that these cells may project to distant brainstem targets, in addition to providing a minor proportion of the local cholinergic innervation of the medial medullary reticular formation.(ABSTRACT TRUNCATED AT 400 WORDS)
Neuroscience, 1992
Acetylcholine has long been known to play an important role in the cortical activation that accom... more Acetylcholine has long been known to play an important role in the cortical activation that accompanies the states of wakefulness and paradoxical sleep (for review, see Refs 17, 21) when this neurotransmitter is released from the cerebral cortex at the highest rates. The major supply of acetylcholine to the cerebral cortex arises from the cholinergic neurons of Meynert's Basal-ganglion or nucleus basalis of the forebrain. Lying in the substantia innominata within the major ascending pathway from the brain stem reticular formation, magnocellular basalis neurons project upon the cerebral cortex as the important ventral, extrathalamic relay of the ascending reticular activating system. Although the cholinergic basalis nucleus neurons have been shown to be important for cortical activation, the precise manner in which they influence cortical activity has not as yet been elucidated, in part because the cholinergic cells of this nucleus have not been identified in electrophysiological studies. Using intracellular recording in guinea-pig brain slices, we were able to record and fill with biocytin nucleus basalis neurons which were subsequently revealed by immunohistochemical staining to be choline acetyltransferase-positive and thus cholinergic. The cholinergic cells displayed rhythmic bursting activity mediated by a low-threshold calcium spike in vitro, which would endow them with a capacity for phasic (in addition to tonic) firing in vivo. By virtue of these different modes, cholinergic basalis neurons may accordingly deter or facilitate the cortical response to sensory input and may furthermore modulate the major frequencies of cortical activity across the different states of the sleep-waking cycle.
Neuroscience, 2012
Orexin (Orx or hypocretin) is critically important for maintaining wakefulness, since in its abse... more Orexin (Orx or hypocretin) is critically important for maintaining wakefulness, since in its absence, narcolepsy with cataplexy occurs. In this role, Orx-containing neurons can exert their influence upon multiple targets through the brain by release of Orx but possibly also by release of other neurotransmitters. Indeed, evidence was previously presented to suggest that Orx terminals could utilize glutamate (Glu) in addition to Orx as a neurotransmitter. Using fluorescence and confocal laser scanning microscopy, we investigated whether Orx varicosities contain the presynaptic markers for synaptic release of Glu or GABA and come into contact with postsynaptic markers for excitatory synapses within the locus coeruleus of the rat brain. We found that a proportion of the Orx+ varicosities were immunostained for the vesicular transporter for Glu, VGluT2. None were immunostained for VGluT1 or VGluT3 or for the vesicular transporter for GABA, VGAT. Among the Orx+ varicosities, 4% of all and 28% of large varicosities contained VGluT2. A similar proportion of the large Orx+ varicosities contained synaptophysin, a presynaptic marker for synaptic vesicles. Orx+ varicosities also contacted elements immunostained for PSD-95, a postsynaptic marker for glutamatergic synapses. We thus conclude that synaptic release of Glu occurs from Orx terminals within the locus coeruleus and can thus be important for the engagement of noradrenergic neurons in stimulating and maintaining arousal.
The Journal of Comparative Neurology, 1994
Within the basal forebrain, y-aminobutyric acid (GABA)-synthesizing neurons are codistributed wit... more Within the basal forebrain, y-aminobutyric acid (GABA)-synthesizing neurons are codistributed with acetylcholine-synthesizing neurons (Gritti et al. 119931 J. , which constitute one of the major forebrain sources of subcortical afferents to the cerebral cortex, In the present study, descending projections of the GABAergic and cholinergic neurons were investigated to the lateral posterior hypothalamus (LHp) through which the medial forebrain bundle passes and where another major forebrain source of subcortical afferents is situated. Retrograde transport of cholera toxin b subunit (CT) from the LHp was combined with immunohistochemical staining for glutamic acid decarboxylase (GAD) and choline acetyl transferase (ChAT) using a sequential peroxidase-antiperoxidase (PAP) technique.
The Journal of Comparative Neurology, 2008
Acetylcholine (ACh) plays an important role in the promotion of paradoxical sleep (PS) with muscl... more Acetylcholine (ACh) plays an important role in the promotion of paradoxical sleep (PS) with muscle atonia through the muscarinic-2 receptor (M2R) in the mesopontine tegmentum. Conversely, orexin (Orx or hypocretin) appears to be critical for the maintenance of waking with muscle tone through the orexin-2 (or hypocretin-B) receptor (Orx2R), which is lacking in dogs having narcolepsy with cataplexy. In dual-immunostained material viewed under fluorescence microscopy, we examined the presence and distribution of M2R or Orx2R labeling on all neuronal nuclei (NeuN)-stained neurons or on glutamic acid decarboxylase (GAD)-stained neurons through the mesopontine tegmentum. Applying stereological analysis, we determined that many neurons bear M2Rs on their membrane (Ϸ6,300), including relatively large, non-GABAergic cells, which predominate (Ͼ75%) in the oral and caudal pontine (PnO and PnC) reticular fields, and small, GABAergic cells (Ϸ2,800), which predominate (Ͼ80%) in the mesencephalic (Mes) reticular formation. Many neurons bear Orx2Rs on their membrane (Ϸ6,800), including relatively large, non-GABAergic cells, which predominate (Ͼ70%) through all reticular fields, and comparatively few GABAergic cells (Ϸ700). In triple-immunostained material viewed by confocal microscopy, many large neurons in PnO and PnC appear to bear both M2Rs and Orx2Rs on their membrane, indicating that ACh and Orx could exert opposing influences of inhibition vs. excitation on putative reticulo-spinal neurons and thus attenuate vs. facilitate activity and muscle tone. A few GABAergic cells bear both receptors and could as PS inhibitor neurons serve under these different influences to control PS effector neurons and accordingly gate PS and muscle atonia appropriately across sleep-wake states.
The Journal of Comparative Neurology, 1997
The Journal of Comparative Neurology, 1995
The present study was undertaken to determine the frequency and distribution of GABAergic neurons... more The present study was undertaken to determine the frequency and distribution of GABAergic neurons within the rat pontomesencephalic tegmentum and the relationship of GABAergic cells to cholinergic and other tegmental neurons projecting to the hypothalamus. In sections immunostained for glutamic acid decarboxylase (GAD), large numbers of small GAD-positive neurons ( -50,000 cells) were distributed through the tegmentum and associated with a high density of GADpositive varicosities surrounding both GAD-positive and GADnegative cells. Through the reticular formation, ventral tegmentum, raphe nuclei, and dorsal tegmentum, GAD-positive cells were codistributed with larger cells, which included neurons immunostained on adjacent sections for glutamate, tyrosine hydroxylase (TH), serotonin, or choline acetyltransferase (ChAT). In sections dual-immunostained for GAD and ChAT, GABAergic neurons were seen to be intermingled with less numerous cholinergc cells ( -2,600 GAD+ to -1,400 ChAT+ cells in the laterodorsal tegmental nucleus, LDTg).
The Journal of Comparative Neurology, 2003
The basal forebrain (BF) plays an important role in modulating cortical activity and facilitating... more The basal forebrain (BF) plays an important role in modulating cortical activity and facilitating processes of attention, learning, and memory. This role is subserved by cholinergic neurons but also requires the participation of other noncholinergic neurons. Noncholinergic neurons include ␥-amino butyric acidergic (GABAergic) neurons, some of which project in parallel with the cholinergic cells to the cerebral cortex, others of which project caudally or locally. With the original aim of distinguishing different subgroups of GABAergic neurons, we examined immunostaining for the calcium binding proteins (CBPs) parvalbumin (Parv), calbindin (Calb), and calretinin (Calret) in the rat. Although the CBP ϩ cell groups were distributed in a coextensive manner with the GABAergic cells, they were collectively more numerous. Of cells retrogradely labeled with cholera toxin (CT) from the prefrontal or parietal cortex, Parv ϩ and Calb ϩ cells, but not Calret ϩ cells, represented substantial proportions (ϳ35-45% each) that collectively were greater than that of GABAergic projection neurons. From dual immunostaining for the CBPs and glutamic acid decarboxylase (GAD), it appeared that the vast majority (Ͼ90%) of the Parv ϩ group was GAD ϩ , whereas only a small minority (Ͻ10%) of the Calb ϩ or Calret ϩ group was GAD ϩ . Significant proportions of Calb ϩ (Ͼ40%) and Calret ϩ (Ͼ80%) neurons were immunopositive for phosphate-activated glutaminase, the synthetic enzyme for transmitter glutamate. The results suggested that, whereas Calret ϩ cells predominantly comprise caudally or locally projecting, possibly glutamatergic BF neurons, Parv ϩ cells likely comprise the cortically projecting GABAergic BF neurons and Calb ϩ cells the cortically projecting, possibly glutamatergic BF neurons that would collectively participate with the cholinergic cells in the modulation of cortical activity.
The Journal of Comparative Neurology, 1993
In recent years, GABAergic neurons have been identified in the basal forebrain where cholinergic ... more In recent years, GABAergic neurons have been identified in the basal forebrain where cholinergic cortically projecting neurons are located and known to be important in mechanisms of cortical activation. In the present s h d y in the rat, the relationship of the GABA-synthesizing neurons to the acetylcholine-synthesizing neurons was examined by application of a sequential double staining immunohistochemical procedure involving the peroxidase-antiperoxidase technique for glutamic acid decarboxylase (GAT-)) and choline acetyltransferase ( C U T ) . In these double and adjacent single immunostained series of sections! the GAD+ and ChAT+ cells were mapped, counted and measured with the aid ofa computerized image analysis system.
The Journal of Comparative Neurology, 1991
GABA-synthesizing neurons were identified in the medulla of the rat by peroxidase-antiperoxidase ... more GABA-synthesizing neurons were identified in the medulla of the rat by peroxidase-antiperoxidase (PAP) immunohistochemistry for glutamic acid decarboxylase (GAD). Using diaminobenzidine (DAB) either alone or intensified with silver, a relatively large number of GAD-immunoreactive neurons were evident within the reticular formation, raphe nuclei and vestibular nuclei. In all these areas, profuse GAD-immunoreactive varicosities appeared to contact the soma and dendrites of both non-GABA and GABA neurons. These observations suggest that GABA neurons may act as interneurons or local projection neurons within the medulla and accordingly exert a potent inhibitory and/or disinhibitory control on bulbar projection neurons. Within the ventral reticular formation (pars alpha and ventralis of the gigantocellular reticular field) and raphe magnus, large numbers of prominent GAD-immunoreactive neurons resembled in size and morphology and overlapped in distribution the serotonin-immunoreactive neurons of the same regions. However, by sequential double immunostaining utilizing DAB as a chromogen for serotonin (5-HT) and benzidine dihydrochloride (BDHC) for GAD, it was found that GAD-containing neurons were distinct from 5-HT-containing neurons. Following injections of wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP) into the upper cervical spinal cord and combined processing for WGA-HRP (using tetramethylbenzidine [TMB] with cobalt) and immunohistochemistry (with DAB), a contingent of spinally projecting neurons were found to contain GAD. The GAD-immunoreactive reticulo- and raphe-spinal neurons were most frequent within the pars alpha and ventralis of the gigantocellular reticular fields and the raphe magnus, where they were approximately equal in number to the coexistent, but distinct 5-HT spinally projecting neurons. GABA neurons of the medulla may thus contribute directly to the bulbar inhibitory influence upon spinal sensory and motor systems.
European Journal of Neuroscience, 2002
Evidence suggests that dopaminergic neurons of the ventral mesencephalic tegmentum (VMT) could be... more Evidence suggests that dopaminergic neurons of the ventral mesencephalic tegmentum (VMT) could be important for paradoxical sleep (PS). Here, we examined whether dopamine (DA) and adjacent g-aminobutyric acid (GABA)-synthesizing neurons are active in association with PS recovery as compared to PS deprivation or control conditions in different groups of rats by using c-Fos expression as a re¯ection of neural activity, combined with dual immunostaining for tyrosine hydroxylase (TH) or glutamic acid decarboxylase (GAD). Numbers of TH + /c-Fos + neurons in the substantia nigra (SN) were not signi®cantly different across groups, whereas those in the ventral tegmental area (VTA) were signi®cantly different and greatest in PS recovery. Numbers of GAD + /c-Fos + neurons in both VTA and SN were greatest in PS recovery. Thus, DA neuronal activity does not appear to be suppressed by local GABAergic neuronal activity during PS but might be altered in pattern by this inhibitory as well as other excitatory, particularly cholinergic, inputs such as to allow DA VTA neurons to become maximally active during PS and thereby contribute to the unique physiological and cognitive aspects of that state.
European Journal of Neuroscience, 2005
Though overlapping in distribution within the posterior hypothalamus, neurons containing orexin (... more Though overlapping in distribution within the posterior hypothalamus, neurons containing orexin (Orx) and melanin concentrating hormone (MCH) may play different roles in the regulation of behavioural state. In the present study in rats, we tested whether they express c-Fos differently after total sleep deprivation (SD) vs. sleep recovery (SR). Whereas c-Fos expression was increased in Orx neurons after SD, it was increased in MCH neurons after SR. We reasoned that Orx and MCH neurons could be differently modulated by noradrenaline (NA) and accordingly bear different adrenergic receptors (ARs). Of all Orx neurons (estimated at 6700), substantial numbers were immunostained for the a 1A -AR, including cells expressing c-Fos after SD. Yet, substantial numbers were also immunostained for the a 2A -AR, also including cells expressing c-Fos after SD. Of all MCH neurons (estimated at 12 300), rare neurons were immunostained for the a 1A -AR, whereas significant numbers were immunostained for the a 2A -AR, including cells expressing c-Fos after SR. We conclude that Orx neurons may act to sustain waking during sleep deprivation, whereas MCH neurons may act to promote sleep following sustained waking. Some Orx neurons would participate in the maintenance of waking during deprivation when excited by NA through a 1 -ARs, whereas MCH neurons would participate in sleep recovery after deprivation when released from inhibition by NA through a 2 -ARs. On the other hand, under certain conditions, Orx neurons may also be submitted to an inhibitory influence by NA through a 2 -ARs.
Neuroscience, Jan 28, 2006
The basal forebrain (BF) plays an important role in modulating cortical activity and influencing ... more The basal forebrain (BF) plays an important role in modulating cortical activity and influencing attention, learning and memory. These activities are fulfilled importantly yet not entirely by cholinergic neurons. Noncholinergic neurons also contribute and comprise GABAergic neurons and other possibly glutamatergic neurons. The aim of the present study was to estimate the total number of cells in the BF of the rat and the proportions of that total represented by cholinergic, GABAergic and glutamatergic neurons. For this purpose, cells were counted using unbiased stereological methods within the medial septum, diagonal band, magnocellular preoptic nucleus, substantia innominata and globus pallidus in sections stained for Nissl substance and/or the neurotransmitter enzymes, choline acetyltransferase (ChAT), glutamic acid decarboxylase (GAD) or phosphate-activated glutaminase (PAG). In Nissl-stained sections, the total number of neurons in the BF was estimated as approximately 355,000 a...
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Papers by Lynda Mainville