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PubMed2005

Multiple types of sensory neurons respond to irritating volatile organic compounds (VOCs): calcium fluorimetry of trigeminal ganglion neurons.

Many volatile organic compounds (VOCs) are significant environmental irritants that stimulate somatosensory nerve endings to produce pain and irritation. We measured intracellular calcium in cultured trigeminal ganglion neurons to characterize the cellular mechanisms and chemical structural determinants underlying sensitivity to VOCs. Trigeminal neurons responded to homologous series of alcohols (C4-C7) as well as saturated and unsaturated aldehydes in a concentration dependent manner. Ranked in terms of threshold to recruit neurons by compounds of the same carbon chain length, enaldehyde<aldehyde<alcohol. Unlike aldehydes and alcohols that displayed ascending concentration curves, recruitment of neurons by enaldehydes (C4-C7) appeared to saturate, consistent with a mechanism that is restricted in its neural distribution. Using pentanol, pentanal and pentenal as model compounds, we found that many but not all cool/cold-sensitive and capsaicin-sensitive neurons responded with increases in intracellular calcium. These VOCs also stimulated other neurons that were insensitive to cooling and capsaicin. Because not all cooling- and all capsaicin-sensitive neurons responded to the model VOCs, it is highly unlikely that known nociceptive ion channels such as TRPV1 or TRPA1 mediate sensitivity to these compounds. For pentanol, pentanal and pentenal, induced calcium influx was dependent on the presence of extracellular calcium. Responses of all neurons to pentanal and pentenal were also dependent upon extracellular sodium. Responses to pentanol were variably dependent on sodium. The distribution of sensitivity suggests that VOC irritation may be mediated by an as yet unidentified mechanism(s) that is/are distributed across different modalities of neurons.

Aldehydes↗
PubMed2004

Neurotoxic effects of trimethyltin and triethyltin on human fetal neuron and astrocyte cultures: a comparative study with rat neuronal cultures and human cell lines.

Trimethyltin (TMT) and triethyltin (TET) caused cell death in cultures of primary human neurons and astrocytes, rat neurons and human neuroblastoma cell lines. Human neurons and astrocytes showed a delayed response to TMT cytotoxicity. After 24h of TMT exposure, LC50 values were 148.1, 335.5 and 609.7 microM for SK-N-MC neuroblastoma cell line, neurons and astrocytes, respectively. Over 5 days of exposure, the cytotoxic potency of TMT increased about 70-fold in human cortical neurons. Rat hippocampal neurons were the most vulnerable cells to TMT cytotoxicity, exhibiting an LC50 value 30-fold lower (1.4 microM) than that of rat cerebellar granule cells (44.28 microM). With the exception of rat hippocampal neurons, TET was more potent than TMT in inducing cell death (LC50 values of 3.5-16.9 microM). Moreover, TET was more effective than TMT in increasing intracellular free Ca2+ concentration in human and rat neurons. This work shows that human fetal neuron and astrocyte cultures are a useful model for studying the neurotoxic effects of these environmental contaminants and, thus, predicting their impact on human health.

Animals↗
PubMed1997

Audiogenic kindling increases neuronal responses to acoustic stimuli in neurons of the medial geniculate body of the genetically epilepsy-prone rat.

Frequent repetition of audiogenic seizure (AGS) ('AGS kindling') in the severe substrain of genetically epilepsy-prone rats (GEPR-9s) results in the appearance of cortical epileptiform electrographic activity, increases of seizure duration and additional convulsive behaviors. These findings suggest that the initial AGS network, which is located primarily in the brainstem, has undergone expansion to the forebrain. The medial geniculate body (MGB) is a thalamic structure that is the first major auditory nucleus efferent to the AGS-initiating site in the inferior colliculus. The MGB is not required for AGS induction, but it has been implicated in the expanded AGS network in GEPR-9s based on focal, pharmacological blockade experiments. The present study examined changes in acoustically evoked MGB neuronal responses in awake and behaving GEPR-9s and in anesthetized GEPR-9s after 14 repetitive AGS-inducing stimuli given daily. An elevated number of action potentials was observed in the MGB neuronal responses after AGS kindling in GEPR-9s. This increase of MGB neuronal responses was associated with a loss of habituation and lasted for at least 28 days after the 14th AGS. An increase in the incidence of sustained acoustic responses in MGB neurons was observed after repetitive AGS in GEPR-9s. Increases in the peak latency and threshold of MGB neuronal responses were also observed after AGS kindling. MGB neurons exhibited a rapid tonic firing during tonic seizures in behaving GEPR-9s, suggesting that the MGB may be implicated in the propagation of seizure activity. However, MGB neuronal firing was silent during post-tonic clonus, a behavior seen in GEPR-9s only after AGS repetition, suggesting that MGB does not play a direct role in the generation of this convulsive behavior. Thus, changes in neuronal firing in nuclei efferent to the MGB, in the expanded neuronal network for repetitive AGS, may be responsible for the generation of post-tonic clonus in GEPR-9s.

Acoustic Stimulation↗
PubMed1998

Bcl-2 accelerates the neuronal differentiation: new evidence approaching to the biofunction of bcl-2 in the neuronal system.

The proto-oncogene product Bcl-2 is unique in that it inhibits apoptosis rather than promoting cell proliferation. In the present study, we encountered a new possible role of Bcl-2 in the neuronal differentiation. Rat pheochromocytoma PC12 cells have been known as the model of neuronal differentiation by the stimulation of NGF. Bcl-2 transfected PC12 (MB2) cells showed the accelerated neuronal differentiation, as compared with control PC12 (V4) cells. In addition, chemotherapeutic agents Taxol which has been known as neurotoxic compound, induced the acute neuronal cell atrophy and suppressed neuronal differentiation. This neuronal cell atrophy and suppression of neuronal differentiation were not due to apoptotic cell death. Interestingly, Bcl-2 rescued PC12 cells from both neuronal cell atrophy and suppression of neuronal differentiation. Taxol suppressed polymerization between neurofilament light and heavy (NF-L and NF-H), and MB2 cell extract rescued it. We, therefore, suggest the acceleration of polymerization between NF-L and NF-H as the new possible role of Bcl-2.

Animals↗
PubMed1999

Neurons in the deep layers of superior colliculus play a critical role in the neuronal network for audiogenic seizures: mechanisms for production of wild running behavior.

Recent investigations suggest that the deep layers of superior colliculus (DLSC) play a role in the neuronal network for audiogenic seizures (AGS). The present study examined DLSC neuronal firing and convulsive behavior simultaneously in freely-moving genetically epilepsy-prone rats (GEPR-9s) using chronically implanted microwire electrodes. An abrupt onset of acoustically-evoked firing at approximately 80-90 dB was observed in DLSC neurons of GEPR-9s, which was significantly above the normal threshold. DLSC neurons began to exhibit rapid tonic burst firing 1-2 s prior to the onset of the wild running behavior at the beginning of AGS. As the tonic phase of the seizure began, DLSC firing ceased, and only returned towards normal following post-ictal depression. These neuronal mechanisms may be relevant to other seizure models in which the DLSC is implicated. The temporal pattern of neuronal firing during AGS is specific to DLSC and differs markedly from those observed elsewhere in the AGS neuronal network. The temporal firing pattern suggests that the DLSC plays a primary role in the generation of the wild running phase of AGS. Previous studies indicate that the inferior colliculus is dominant during AGS initiation, and the pontine reticular formation is dominant during the tonic extension phase of AGS. Taken together these data suggest that the neurons in the neuronal network undergo a dominance shift as each specific convulsive behavior of AGS is elaborated.

Acoustic Stimulation↗
PubMed1999

Increased c-fos expression in spinal lumbosacral projection neurons and preganglionic neurons after irritation of the lower urinary tract in the rat.

Chemical irritation of the lower urinary tract (LUT) induces c-fos expression in neurons in the lumbosacral (L(6) and S(1)) spinal cord. This study used axonal tracing with fluorescent dyes to identify the types of spinal neurons expressing Fos immunoreactivity (IR) after LUT irritation in the rat. Fos-IR was detected in lateral and medial superficial dorsal horn, the sacral parasympathetic nucleus (SPN) and lamina X around the central canal. Fos-IR was detected in spinal neurons projecting to supraspinal sites (brainstem and hypothalamus), in preganglionic neurons (PGN) and in unlabeled segmental interneurons. A substantial percentage (20%) of dye labeled PGN exhibited Fos-IR after LUT irritation; and a larger percentage (36%) exhibited Fos-IR after electrical stimulation of the pelvic nerve which contains afferent pathways from all of the pelvic organs. The majority (average 55%) of Fos-positive neurons projecting to supraspinal sites were also located in the region of the SPN. A selective distribution of different types of neurons was detected in this region: PGN were located ventral to the spinal projection neurons which in turn were located ventral to the majority of unidentified Fos-positive neurons. The distribution of Fos-positive PGN and projection neurons was similar in spinal intact and spinal transected animals indicating that c-fos expression was mediated by monosynaptic afferent input or input from segmental interneurons and was not due to activation of supraspinal micturition reflex pathways.

Animals↗
PubMed1999

Firing of putative cholinergic neurons and micturition center neurons in the rat laterodorsal tegmentum during distention and contraction of urinary bladder.

The relation between unit activity in the laterodorsal tegmental (LDT) area and the state of the urinary bladder was examined in urethane-anesthetized rats. Neurons in the LDT area can be classified into two populations: broad-spike (possibly cholinergic) and brief-spike (non-cholinergic). When the rats showed cortical electroencephalographic activity with large amplitude lower frequency, indicative of deep anesthesia, more than 40% of the broad-spike neurons was excited and about 10% was inhibited by infusion of saline into the bladder. The response was followed by decrease in amplitude and slight increase in frequency of the cortical activity, i.e., lightening of anesthesia. During light anesthesia, excitation was observed only in less than 10% of the units, while 17% was inhibited. In the brief-spike neurons, a similar proportion (about 20%) was excited and less than 10% was inhibited by the distention during either state of anesthesia. About 10% of the broad-spike neurons in the LDT area and 30% of the brief-spike neurons examined were discharged prior to the bladder contraction. Such neurons of the brief-spike category were encountered frequently outside of the central gray; lateral, caudal and ventral to the main mass of cholinergic neurons in the LDT area. These results suggest the possible involvement of the broad-spike (cholinergic) neurons in the elevation of vigilance level caused by bladder distention. The brief-spike (non-cholinergic) neurons firing with relation to bladder contraction may be part of the micturition reflex center.

Action Potentials↗
PubMed1999

Drosophila neurons respond differently to hypoxia and cyanide than rat neurons.

Compared with mammalian species, Drosophila melanogaster exhibits marked tolerance to hypoxia or anoxia. However, the underlying cellular mechanisms of tolerance are still largely unknown. In order to assess the electrophysiologic response to O(2) lack in Drosophila neurons and compare them to those in mammals, we used neurons from embryonic cultures of both Drosophila and rat. We studied the effects of hypoxia on membrane potential V(m), input resistance R(m), rheobase, and action potential characteristics before, during and after 3 to 5 min of hypoxia (measured PO(2)<20 Torr). In Drosophila neurons, on the one hand, V(m) reversibly hyperpolarized with hypoxia by an average of about 20 mV and input resistance decreased by 71% from control. In most cells studied, action potential (AP) amplitude decreased, its duration increased, and its threshold shifted in a hyperpolarized direction before AP generation was attenuated. On the other hand, V(m) in rat cortical neurons reversibly depolarized by an average of 10 mV with hypoxia. Input resistance was reversibly reduced by 58% and, in most cells studied, AP amplitude also decreased and its duration increased. In contrast to the effects of hypoxia on V(m), CN caused a depolarization by 22 mV and a slight increase in R(m) in Drosophila. In the rat, CN was similar to hypoxia in its effect on R(m). We conclude that (1) rat and Drosophila neurons decrease their excitability in hypoxia by activating different mechanisms; (2) the most likely explanation for the hyperpolarization and the decrease in R(m) in Drosophila neurons is the activation of a K(+) conductance; this activation, by itself, cannot explain the results in rat neurons and (3) hypoxia and cyanide have similar effects in rat neurons but are divergent in their effects in Drosophila neurons.

Animals↗
PubMed1991

Noradrenergic locus coeruleus neurons: their distant connections and their relationship to neighboring (including cholinergic and GABAergic) neurons of the central gray and reticular formation.

Noradrenergic LC neurons appear to be relatively unique in the brain, being unsurpassed in the divergence and ubiquity of their projections through the central nervous system. In this regard, they share certain characteristics with peripheral noradrenaline neurons of the sympathetic nervous system. As such they would be assumed to play a very general role in modulating the activity of large populations of neurons in multiple, functionally diverse systems. Like other periventricular and reticular neurons, they have the potential to receive afferent information from multiple sources via long dendrites, upon which the majority of their inputs from brainstem and forebrain may arrive. They appear closely related to the cholinergic neurons of the laterodorsal tegmental nucleus, their neighbors that are located medial and rostral to them within the periventricular gray and that have similarly oriented and positioned long dendrites that would allow reception of similar afferent input as the LC neurons and also possibly interaction with the LC neurons. As evidenced by input to the noradrenergic cell bodies in the compact portion of the nucleus, a moderate GABAergic innervation, that may derive in part from local neurons, could have a potent influence on the activity of the cells. Periventricular GABAergic cells could also serve as intermediaries to other afferent input, from a distance, terminating in the periventricular region or from local neurons such as the cholinergic cells of the laterodorsal tegmental nucleus.

Acetylcholine↗
PubMed1997

Enrichment of the fraction of nociceptive neurones in cultures of primary sensory neurones.

A method for enriching the fraction of nociceptive neurones in cultures of primary sensory neurones is described. Neurones from neonatal rat dorsal root ganglia were isolated, layered on 40% Ficoll and centrifuged, separating the neurones into a low density fraction (LDF) and a high-density fraction (HDF). The LDF had a smaller mean diameter (19.7 microm) than the HDF (27.3 microm) and uncentrifuged cells (23.6 microm). The proportion of cells immunoreactive for antibodies to substance P and calcitonin gene-related peptide, both of which are found in nociceptive neurones, was significantly greater in the LDF than in HDF. A substantial enrichment of the proportion of neurones responding to the algogenic substances capsaicin and bradykinin with an increase in intracellular calcium was observed in the LDF. The proportion of capsaicin and bradykinin-responsive neurones was also found to be increased by culturing the neurones, with a particularly pronounced enhancement in the proportion of bradykinin-responsive cells. We conclude that separation on the basis of density followed by culture is a useful way of enriching the proportion of nociceptive neurones for the purpose of electrophysiological, biochemical or other studies.

Animals↗
PubMed2000

Differential gene expression between human neurons and neuronal progenitor cells in culture: an analysis of arrayed cDNA clones in NTera2 human embryonal carcinoma cell line as a model system.

To elucidate the highly complex expression pattern of the genes involved in human neuronal differentiation, differential gene expression between human neurons and neuronal progenitor cells was investigated by analysis of a cDNA expression array in a pluripotent human embryonal carcinoma cell line NTera2 (NT2), a model system of human neuronal differentiation. Among 588 arrayed cDNA clones, 87 genes showed a differential expression pattern between undifferentiated neuronal progenitor cells (NT2-U) and NT2-derived differentiated neurons induced by treatment with retinoic acid (RA) (NT2-N), while 26 genes could not be analyzed due to high background signals. The levels of expression of 76 genes, including those encoding a group of transcription factors, intracellular signal-transducing proteins, cell death-regulatory proteins, and growth factors/cytokines/neurotransmitters and their receptors, were elevated after neuronal differentiation, while the levels of 11 genes, including those coding for cellular proliferation-related proteins, were decreased. Among the differentially expressed genes following induction of neuronal differentiation, significant up-regulation of the growth-associated protein (GAP-43), low-affinity nerve growth factor receptor p75 (LNGFR), and defender against apoptotic cell death (DAD1) mRNAs and substantial down-regulation of the proliferation-associated gene (PAG), fibroblast growth factor receptor-1 (FGFR-1), and cellular RA-binding protein-II (CRABP-II) mRNAs were verified by Northern blot analysis. These results indicate that the analysis of cDNA expression arrays provides a useful approach for screening and identification of a set of distinct genes that undergo highly complex regulation during human neuronal differentiation.

Blotting, Northern↗
PubMed1997

GALR1 galanin receptor mRNA is co-expressed by galanin neurons but not cholinergic neurons in the rat basal forebrain.

The neuropeptide galanin (GAL) has been proposed to be an inhibitory modulator of cholinergic transmission in the hippocampus and may impair memory by directly affecting the activity of basal forebrain (BF) cholinergic neurons. Alternatively, GAL may act indirectly and modulate the activity of other neurotransmitter systems which, in turn, influence cholinergic transmission. We have used double in situ hybridization histochemistry to evaluate the co-expression of the GAL receptor subtype, GALR1, within cholinergic neurons in the medial septum/diagonal band of adult male rats. In alternate brain sections, we assessed the co-expression of GALR1 mRNA within another forebrain cell group implicated in memory functions, the neurons of the bed nucleus of the stria terminalis (BNST) and medial amygdala (AMe) which co-express vasopressin (VP) and GAL and project to septo-hippocampus. Despite the abundance of GALR1 mRNA-expressing neurons in the cholinergic BF, we found no evidence for the co-expression of this receptor subtype within cholinergic neurons in the medial septum/diagonal band. In contrast, we detected an extensive co-expression (95%) of GALR1 mRNA within extrahypothalamic VP/GAL neurons. These results do not support the idea that GAL, acting via the GALR1 receptor, directly impairs BF cholinergic neurons but suggest, instead, that non-cholinergic neurons in the BF may play a role in mediating the inhibitory actions of GAL on cholinergic function. However, our findings provide anatomical evidence that GAL could directly modulate the activity and/or secretion pattern of extrahypothalmic VP/GAL neurons into septo-hippocampal regions.

Acetylcholine↗
PubMed2000

Bidirectional modulation of nociception by GABA neurons in the dorsolateral pontine tegmentum that tonically inhibit spinally projecting noradrenergic A7 neurons.

The A7 catecholamine cell group in the dorsolateral pontine tegmentum constitutes an important part of the descending pathways that modulate nociception. Evidence from immunocytochemical studies demonstrate that noradrenergic A7 neurons are densely innervated by GABA terminals arising from GABA neurons that are located in the dorsolateral pontine tegmentum medial to the A7 cell group. GABA(A) receptors are also located on the somata and dendrites of noradrenergic A7 neurons. These findings suggest that noradrenergic neurons in the A7 cell group may be under tonic inhibitory control by GABA neurons. To test this hypothesis, the GABA(A) antagonist bicuculline methiodide in doses of 0.2 or 1.0nmol was microinjected into sites located dorsal to the A7 cell group and the resulting effects on tail flick and nociceptive foot withdrawal responses were measured. Both doses of bicuculline produced significant increases in tail flick latencies and small, but significant, increases in foot withdrawal latencies. Intrathecal injection of the alpha(2)-adrenoceptor antagonist yohimbine, in a dose of 76.7nmol (30microg), attenuated the antinociceptive effect of bicuculline on both the tail and the feet. In contrast, the alpha(1)-adrenoceptor antagonist WB4101, in a nearly equimolar dose of 78.6nmol (30microg), increased the antinociceptive effect of bicuculline on both the tail and the feet. Intrathecal injection of the antagonists alone did not consistently alter nociceptive responses of either the feet or the tail. These findings suggest that noradrenergic neurons in the A7 cell group are tonically inhibited by local GABA neurons. Furthermore, these findings suggest that inhibition of GABA(A) receptors located on spinally-projecting A7 noradrenergic neurons disinhibits, or activates, two populations of A7 neurons that have opposing effects on nociception. One of these populations facilitates nociception by an action mediated by alpha(1)-adrenoceptors in the spinal cord dorsal horn and the other population inhibits nociception by an action mediated by alpha(2)-adrenoceptors.

Adrenergic alpha-Antagonists↗
PubMed1997

Veratridine delays apoptotic neuronal death induced by NGF deprivation through a Na(+)-dependent mechanism in cultured rat sympathetic neurons.

Superior-cervical ganglion (SCG) cells dissociated from newborn rats depend on nerve growth factor (NGF) for survival. Membrane depolarization with elevated K+ is known to prevent neuronal death following NGF deprivation and/or to promote survival via a Ca(2+)-dependent mechanism. Here we have exploited the possibility of whether or not a Na(+)-dependent pathway for neuronal survival is present in these cells. Veratridine (EC50 = 40 nM), a voltage-dependent Na+ channel activator, significantly delayed the onset of apoptotic cell death in NGF-deprived SCG neurons that had been cultured for 7 days in the presence of NGF. This effect was blocked completely by Na+ channel blockers including tetrodotoxin (TTX, 1 microM), benzamil (25 microM) and flunarizine (1 microM), but was not attenuated by nimodipine (1 microM), an L-type Ca2+ channel blocker. The saving effect of veratridine on cultured neurons was observed even in low Ca2+ media (0-1.0 mM), but was completely abolished in a low Na+ medium (38 mM). Sodium-binding benzofuran is isophthalate was employed as a fluorescent probe for monitoring the level of cytoplasmic free Na+, which revealed a sustained increase in its level (12.9 mM, 307% of that of control) in response to veratridine (0.75 microM). The TTX or flunarizine completely blocked veratridine-induced Na+ influx in these cultured neurons. Moreover, no appreciable increase in intracellular Ca2+ was detected under these conditions. Though Na+ channels were effectual in SCG neurons which were freshly isolated from newborn rats, the Na(2+)-dependent saving effect of veratridine was not observed in these young neurons. These lines of evidence suggest that the death-suppressing effect of veratridine on cultured SCG neurons depends on the Na+ influx via voltage-dependent Na+ channels, and suggest the presence of Na(+)-dependent regulatory mechanism(s) in neuronal survival.

Animals↗
PubMed2003

Neurons and astrocytes secrete factors that cause stem cells to differentiate into neurons and astrocytes, respectively.

We examined the role of soluble factors secreted by neurons and astrocytes in the differentiation of CNS stem cells. We showed that the soluble factors from neurons strongly induced multipotent cortical stem cells to acquire neuronal identity, while the factors from astrocytes promoted astrocytic differentiation. Neurons secreted the brain-derived neurotrophic factor and neurotrophin-3 to induce neuron differentiation, while astrocytes secreted ciliary neurotrophic factor for astrocyte differentiation. Both neurons and astrocytes secrete bone morphogenetic proteins (BMPs). Using BMP antagonists it was shown that BMPs were responsible for the neuron-induced neuronal differentiation, as well as the astrocyte-induced astrocytic differentiation. These findings demonstrate the importance of soluble signals in lineage-specific differentiation and provide evidence for the roles of neurons and astrocytes in stem cell differentiation.

Animals↗
PubMed2004

Neuron production, neuron number, and structure size are seasonally stable in the hippocampus of the food-storing black-capped chickadee (Poecile atricapillus).

Neuronal recruitment in the black-capped chickadee (Poecile atricapillus) hippocampus occurs at a higher rate in the fall than at other times of the year. As a means of determining whether this increase in recruitment results from greater neuron production, chickadees were caught in the wild between October and March and injected with the cell-birth marker 5-bromo-2'-deoxyuridine. Two weeks later, birds were killed by overdose, and hippocampal neuron production, apoptosis, neuron number, and hippocampal volume were determined. Chickadees collected in October, November, January, February, and March did not differ in neuron production, apoptosis, hippocampal volume, or neuron number. These findings indicate that increases in neuronal recruitment in the chickadee hippocampus in the fall do not result from increased neuron production, but instead, enhanced survival of new neurons.

Animals↗
PubMed1993

Hilar somatostatin neurons are more vulnerable to an ischemic insult than CA1 pyramidal neurons.

The effects of a very short ischemic insult on hilar somatostatin (SS) neurons were investigated in the gerbil hippocampus by means of immunocytochemistry and in situ hybridization histochemistry. A selective and significant loss of 40% of hilar SS neurons took place after 1 day, and a 60% loss after 7 days following 2 min of ischemia, while no SS neurons were lost during recirculation after 1 min of ischemia. Repeated 2-min periods of ischemia, which induced ischemic tolerance by vulnerable CA1 neurons, caused almost complete loss of hilar SS neurons. This study clearly demonstrates that hilar SS neurons are more vulnerable to ischemic insult than CA1 pyramidal neurons. Ischemic tolerance may be induced during the progressive loss of SS neurons in the hilus by changes in their synaptic connections to CA1 pyramidal neurons.

Animals↗
PubMed2005

The hippocampus modulates dopamine neuron responsivity by regulating the intensity of phasic neuron activation.

Aberrant dopamine (DA) signaling has been advanced as a contributing factor to the pathophysiology of a number of psychiatric conditions including schizophrenia; however, the many factors involved in regulating DA system responsivity have not been completely delineated to date. We have shown previously that DA neuron activity states are independently regulated by distinct afferent pathways. We now provide evidence that these pathways interact to control the population of neurons that are phasically activated. As shown previously, infusions of NMDA into the ventral subiculum (vSub) increases the number of spontaneously active DA neurons (population activity), while having no effect on firing rate or average bursting activity. In contrast, NMDA activation of the pedunculopontine tegmental nucleus (PPTg) results in a significant increase in DA neuron burst firing without significantly affecting population activity. However, simultaneous excitation of the vSub and PPTg induces a significant increase in both DA neuron population activity and burst firing resulting in a approximately 4-fold increase in the number of high-bursting neurons observed per electrode track. These data suggest that DA neuron population activity is not simply associated with the tonic release of DA in forebrain regions, but rather represents a recruitable pool of DA neurons that can be further modulated by excitatory inputs to induce a graded phasic response. Taken as a whole, we propose that the synchronous activity of distinct afferent inputs to the VTA phasically activates selective populations of DA neurons, and hence may be a site of pathological regulation underlying aberrant DA signaling.

Action Potentials↗