Transient Increase In Firing Rate Research Articles

Substantia Nigra Dopamine Neuronal Responses to Habenular Stimulation and Foot Shock Are Altered by Lesions of the Rostromedial Tegmental Nucleus

Dopamine (DA) neurons of the substantia nigra (SN) and ventral tegmental area generally respond to aversive stimuli or the absence of expected rewards with transient inhibition of firing rates, which can be recapitulated with activation of the lateral habenula (LHb) and eliminated by lesioning the intermediating rostromedial tegmental nucleus (RMTg). However, a minority of DA neurons respond to aversive stimuli, such as foot shock, with a transient increase in firing rate, an outcome that rarely occurs with LHb stimulation. The degree to which individual neurons respond to these two stimulation modalities with the same response phenotype and the role of the RMTg is not known. Here, we record responses from single SN DA neurons to alternating activation of the LHb and foot shock in male rats. Lesions of the RMTg resulted in a shift away from inhibition to no response during both foot shock and LHb stimulation. Furthermore, lesions unmasked an excitatory response during LHb stimulation. The response correspondence within the same neuron between the two activation sources was no different from chance in sham controls, suggesting that external inputs rather than intrinsic DA neuronal properties are more important to response outcome. These findings contribute to a literature that shows a complex neurocircuitry underlies the regulation of DA activity and, by extension, behaviors related to learning, anhedonia, and cognition.

Chemosensitive Phox2b‐expressing neurons are crucial for hypercapnic ventilatory response in the nucleus tractus solitarius

Central hypercapnic hypoventilation is highly prevalent in children suffering from congenital central hypoventilation syndrome (CCHS). Mutations of the gene for paired-like homeobox 2b (Phox2b) are aetiologically associated with CCHS and Phox2b is present in central components of respiratory chemoreflex, such as the nucleus tractus solitarius (NTS). Injection of the neurotoxin substance P-saporin into NTS destroys Phox2b-expressing neurons. Impaired hypercapnic ventilatory response caused by this neurotoxin is attributable to a loss of CO2 -sensitive Phox2b-expressing NTS neurons. A subgroup of Phox2b-expressing neurons exhibits intrinsic chemosensitivity. A background K+ channel-like current is partially responsible for such chemosensitivity in Phox2b-expressing neurons. The present study helps us better understand the mechanism of respiratory deficits in CCHS and potentially locates a brainstem site for development of precise clinical intervention. The nucleus tractus solitarius (NTS) neurons have been considered to function as central respiratory chemoreceptors. However, the common molecular marker defined for these neurons remains unknown. The present study investigated whether paired-like homeobox 2b (Phox2b)-expressing NTS neurons are recruited in hypercapnic ventilatory response (HCVR) and whether these neurons exhibit intrinsic chemosensitivity. HCVR was assessed using whole body plethysmography and neuronal chemosensitivity was examined by patch clamp recordings in brainstem slices or dissociated neurons from Phox2b-EGFP transgenic mice. Injection of the neurotoxin substance P-saporin (SSP-SAP) into NTS destroyed Phox2b-expressing neurons. Minute ventilation and tidal volume were both reduced by 13% during exposure to 8% CO2 in inspired air when ∼13% of the Phox2b-expressing neurons were eliminated. However, a loss of ∼18% of these neurons was associated with considerable decreases in minute ventilation by ≥18% and in tidal volume by≥22% when challenged by ≥4% CO2 . In both cases, breathing frequency was unaffected. Most CO2 -activated neurons were immunoreactive to Phox2b. In brainstem slices, ∼43% of Phox2b-expressing neurons from Phox2b-EGFP mice displayed a sustained or transient increase in firing rate during physiological acidification (pH7.0 or 8% CO2 ). Such a response was also present in dissociated neurons in favour of an intrinsic property. In voltage clamp recordings, a background K+ channel-like current was found in a subgroup of Phox2b-expressing neurons. Thus, the respiratory deficits caused by injection of SSP-SAP into the NTS are attributable to proportional lesions of CO2 /H+ -sensitive Phox2b-expressing neurons.

Cortical neurons multiplex reward-related signals along with sensory and motor information

Rewards are known to influence neural activity associated with both motor preparation and execution. This influence can be exerted directly upon the primary motor (M1) and somatosensory (S1) cortical areas via the projections from reward-sensitive dopaminergic neurons of the midbrain ventral tegmental areas. However, the neurophysiological manifestation of reward-related signals in M1 and S1 are not well understood. Particularly, it is unclear how the neurons in these cortical areas multiplex their traditional functions related to the control of spatial and temporal characteristics of movements with the representation of rewards. To clarify this issue, we trained rhesus monkeys to perform a center-out task in which arm movement direction, reward timing, and magnitude were manipulated independently. Activity of several hundred cortical neurons was simultaneously recorded using chronically implanted microelectrode arrays. Many neurons (9-27%) in both M1 and S1 exhibited activity related to reward anticipation. Additionally, neurons in these areas responded to a mismatch between the reward amount given to the monkeys and the amount they expected: A lower-than-expected reward caused a transient increase in firing rate in 60-80% of the total neuronal sample, whereas a larger-than-expected reward resulted in a decreased firing rate in 20-35% of the neurons. Moreover, responses of M1 and S1 neurons to reward omission depended on the direction of movements that led to those rewards. These observations suggest that sensorimotor cortical neurons corepresent rewards and movement-related activity, presumably to enable reward-based learning.

Auditory Cortex: Representation through Sparsification?

The recent discovery of combination-sensitive neurons in the primary auditory cortex of awake marmosets may reconcile previous, apparently contradictory, findings that cortical neurons produce strong, sustained responses, but also represent stimuli sparsely.

Simple spike responses of gaze velocity Purkinje cells in the floccular lobe of the monkey during the onset and offset of pursuit eye movements.

1. We recorded the simple spike firing rate of gaze velocity Purkinje cells (GVP-cells) in the flocculus/ventral paraflocculus of two monkeys during the smooth pursuit eye movements evoked by a target that was initially at rest, started suddenly, moved at a constant velocity, and then stopped. 2. For target motion in the preferred direction, GVP-cells showed a large transient increase in firing rate at the onset of pursuit, a smaller but sustained increase during the maintenance of pursuit, and a smooth return to baseline firing with little undershoot at the offset of pursuit. For target motion in the nonpreferred direction, GVP-cells showed a small decrease in firing rate at the onset of pursuit, a similar sustained decrease during the maintenance of pursuit, but a large transient increase in firing rate at the offset of pursuit before returning to baseline firing. 3. We pooled the data in our sample of horizontal GVP-cells by subtracting the population average of firing rate recorded during pursuit in the nonpreferred direction from the population average recorded during pursuit in the preferred direction. We transformed this net population average by passing it through a model of the brain stem final common pathway and the oculomotor plant. This yielded a signal that closely matched the observed trajectory of eye velocity during pursuit. We conclude that the transient overshoots exhibited in the firing rate of GVP-cells can provide appropriate compensation for the lagging dynamics of the oculomotor plant.

Cholecystokinin octapeptide potentiates the inhibitory response mediated by D 2 dopamine receptors in slices of the ventral tegmental area of the brain in the rat

The ability of cholecystokinin octapeptide (CCK8) to modulate dopamine (DA)-induced inhibition of the firing of neurons in the ventral tegmental area of the rat was examined. Extracellular recordings were obtained from putative DA-containing neurons, identified on the basis of their electrophysiological characteristics and response to DA, in an in vitro slice preparation from the ventral tegmental area of the brain. Application of DA produced a concentration-dependent reduction in firing rate. This DA-induced inhibition was mimicked by the D 2 selective agonist, LY 171555 ( trans-(−)-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-2H-pyrazolo[3,4-g]quinoline), but not by the D 1 selective agonist, SKF 38393 (R-(+)-2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine). The DA-induced inhibition was antagonized selectively by the D 2 antagonist, l-sulpiride, but not by the D 1 antagonist, SCH 23390 (R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol). However, CCK8 elicited a transient increase in firing rate in some neurons and, in addition, potentiated the inhibitory response evoked by DA or LY 171555. Again SKF 38393 was without effect following the administration of CCK8. Taken together, these results suggest that DA-induced inhibition of DA-containing neurons in the ventral tegmental area of the brain of the rat is mediated by activation of D 2-receptors and that CCK8 potentiates this D 2-mediated inhibition.

Centre components of cone-driven retinal ganglion cells: differential sensitivity to 2-amino-4-phosphonobutyric acid.

1. Changes in different components of the cone-driven centre responses of cat retinal ganglion cells were studied before and during local application of 2-amino-4-phosphonobutyric acid (APB). Responses were elicited with bar stimuli whose luminance was above ('brighter') or below ('dimmer') the photopic background luminance. The bars were centrally located, and were similar in width to the receptive field centre. 2. APB acted differently on the on- and off-centre cells. For on-centre X and Y cells, all components of the responses to bright and dim bars were diminished by APB. For the off-centre X and Y cells. APB reduced all components except the transient increase in firing rate when the bright bar was turned off or when the dim bar was turned on. 3. These results suggest that the centre response mechanism of off-centre X and Y cells comprises APB-sensitive and APB-resistant components. The APB-sensitive component is more sustained and responds to both brightening and dimming stimuli. The APB-resistant component is more transient and responds primarily to dimming stimuli. For on-centre X and Y cells only APB-sensitive components could be demonstrated. 4. Experiments with stationary sinusoidal gratings modulated at 0.5-10 Hz showed that responses of off-centre cells were more affected by APB at low than at high temporal frequencies, confirming that the APB-sensitive pathway is responsible for more of the low temporal frequency responses. As expected from the responses to bar stimuli, APB had a uniform effect at all temporal frequencies in on-centre cells. 5. For off-centre cells, the APB-sensitive component is probably derived from input from depolarizing bipolar cells, and the APB-resistant component is derived from hyperpolarizing bipolar input, although one or both pathways could also involve amacrine cells. The combination of these pathways increases the range of temporal frequencies to which the cell can respond and also increases the range of response amplitudes. 6. The lack of differential effects on on-centre cells may have several explanations. The most likely explanations are that only depolarizing bipolars contribute significantly to the centre responses of these cells under the conditions of these experiments, or that there is an APB-sensitive synapse somewhere in the retina besides the one from cones to depolarizing bipolars.

Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: studies in the ventral tegmental area

Extracellular single-cell recording and microiontophoretic techniques were used to characterize the effects of cocaine on the activity of mesoaccumbens A10 dopamine (DA) neurons in the rat ventral tegmental area (VTA), which have been implicated in the rewarding effects of this and other drugs of abuse. Because cocaine inhibits the reuptake of DA, norepinephrine (NE), and serotonin (5-HT), and exerts local anesthetic actions, the possible involvement of each of these various mechanisms in the effects of cocaine on A10 DA neurons was investigated. Intravenous administration of cocaine caused a significant, dose-dependent, partial inhibition (50-70%) of the firing of antidromically identified mesoaccumbens DA neurons. Similar partial inhibition of A10 neurons was observed following intravenous administration of nomifensine, GBR-12909, and norcocaine, all of which inhibit DA reuptake. Neither the selective 5-HT uptake inhibitor fluoxetine nor the selective NE uptake inhibitor desmethylimipramine (DMI) inhibited the firing of A10 DA neurons. The local anesthetic agent procaine, which lacks DA uptake blocking efficacy, caused a slight, transient increase in firing rate. These results suggest that the effects of cocaine on A10 DA neurons are due to inhibition of DA reuptake, a conclusion that has been supported by several other findings. Pretreatment with reserpine to deplete vesicular stores of DA significantly reduced the ability of intravenous cocaine to suppress A10 DA neuronal activity. Microiontophoretic administration of cocaine caused only a weak (15-20%) inhibition of the activity of A10 DA neurons, but significantly increased and prolonged the inhibition produced by iontophoretic DA. This effect was not observed with iontophoretically administered procaine iontophoresis of cocaine also significantly potentiated the inhibition of A10 DA activity caused by electrical stimulation of the nucleus accumbens (NAc). Both unilateral ibotenic acid lesions of the NAc and hemitransections of the brain rostral to the VTA significantly reduced the inhibitory effects of intravenous cocaine on A10 DA neurons, suggesting that both somatodendritic impulse-regulating DA autoreceptors and inhibitory NAc-VTA feedback processes are involved in the effects of intravenous cocaine on A10 DA neurons. Therefore, it is hypothesized that the relatively weak inhibitory effects of cocaine on A10 DA neurons may represent a poor compensatory response to enhanced DA neurotransmission within the NAc, and may help to explain the extremely potent rewarding effects of this important drug of abuse.

Effects of endotoxin and sodium salicylate on the preoptic thermosensitive neurons in tissue slices

Effects of E. coli endotoxin and sodium salicylate (Sal) on single-unit activity of thermosensitive neurons recorded in slices of preoptic and anterior hypothalamic area (PO/AH) were studied in vitro. Perfusion of endotoxin-containing Krebs-Ringer's solution or local application of endotoxin in the immediate vicinity of recording neurons decreased and increased the firing rate of 31 of 34 warm-sensitive neurons and a cold-sensitive neuron, but had no effect on the majority of thermally insensitive neurons. In about half of warm-sensitive neurons the inhibitory response to endotoxin was preceded by a transient increase in firing rate. The pyrogen-induced decrease in firing rate in warm-sensitive neurons was reversibly blocked or attenuated by local application of Sal in a dose-dependent manner. The results are consistent with the view that pyrogen and Sal act in the PO/AH to produce fever and antipyresis, respectively, by appropriately offsetting the activity of thermosensitive neurons.

Time course of visual multi-neuronal discharges evoked by eye movements in light

Transient responses in the multineuronal activity along the visual pathways of ‘encéphale isolé’ cats were studied during movements of the eyes across a source of light. The time courses of this activity depended upon selective charcteristics of the ocular movements. When the movements were active and with a fast rising phase of the electro-oculogram, the transient increase in firing rate of the geniculo-cortical tract preceded the burst of activity evoked in the optic chiasm by retinal image shift produced by the eye movement. When the the movements were passive, or if active, had a slow rising phase, the phase response in the optic chiasm appeared before the transient increase in the geniculo-cortical tract. In both rapid and slow movements teh oculomotor activation preceded chiasmatic and lateral geniculate firing. These results are discussed in relation to previous observations in dark-adapted cats of transient increases in geniculo-cortical, cortico-fugal multineuronal activity and in lateral geniculate single units, without changes in the optic chiasm activity, coincident with active and fast eye movements but not with slow or passive ocular movements. The signifance of these observations in relation to the ‘coronally discharge’ hypothesis is also discussed.