Noradrenergic Modulation of Lateral Geniculate Neurons: Physiological and Pharmacological Studies

The physiological actions of norepinephrine (NE) were examined in the rat dorsal lateral geniculate nucleus (LGNd) using extracellular single cell recording and microiontophoresis. Prolonged, low current iontophoretic applications of NE consistently elicited an increase in the firing rate of LGNd neurons which was delayed in onset and prolonged after cessation of the ejection. Sympathomimetic amines other than NE also activated LGNd neurons with varying degrees of effectiveness. On the basis of the relative potencies of a series of these agonists and the ability of iontophoretically applied (alpha)-antagonists to selectively block the facilitatory action of NE, it is concluded that NE acts via an (alpha)(,1)- ( postsynaptic ) adrenoceptor. Systemic administration of the (alpha)-adrenoceptor antagonist WB-4101 also produced a selective blockade of the response to NE. In contrast to NE, serotonin (5-HT) produced a suppression of the firing of LGNd neurons.To examine the effects of NE on evoked activity, identified geniculocortical relay neurons (P-cells) were driven by electrical stimulation of the afferent visual pathway at the level of the optic chiasm. NE caused a marked facilitation of both the short latency (2-4 msec) and the delay (70-230 msec) responses to such stimulation. The (alpha)-adrenoceptor antagonist phentolamine, which by itself had no consistent effect on evoked activity, strongly diminished the response to NE. 5-HT was a powerful depressant of electrically evoked activity; neither phentolamine nor the 5-HT antagonist methysergide antagonized this response. Firing of LGNd units evoked by flashes of light was also facilitated by NE and depressed by 5-HT.When afferent excitation from the retina was eliminated by enucleation of the eyes, many LGNd neurons ceased firing spontaneously. Silent neurons in enucleated animals generally did not respond to NE although the excitatory amino acid glutamate was still highly active. Under these conditions, NE enhanced the excitation produced by glutamate, suggesting that NE increases the general excitability of these neurons and that it acts in a neuromodulatory fashion. The (gamma)-aminobutyric acid (GABA) antagonist picrotoxin, unlike NE, did not facilitate the action of glutamate, indicating that the action of NE is not mediated by suppression of adjacent GABAergic interneurons.Electrical stimulation of the locus coeruleus (LC), which contributes a dense noradrenergic innervation to the LGNd, mimicked the activating effect produced by locally applied NE. The response to 10 Hz trains was generally delayed and the increased rate persisted after the stimulation period. This effect was blocked by iontophoretic application or intravenous administration of WB-4101. Silent cells in enucleated animals were not activated by LC stimulation, but, as with iontophoretic NE, LC stimulation did facilitate the excitatory action of glutamate. WB-4101 blocked both the facilitatory actions of LC stimulation and of iontophretic NE.It is concluded that NE, action via an (alpha)(,1)-adrenoceptor, facilitates the excitability of LGNd relay neurons to afferent stimulation. The close similarity between the effects of locally applied NE and stimulation of the LC provided evidence that NE is a transmitter in the coeruleogeniculate pathway. This pathway may serve to modulate the transmission of visual information from the retina to the strate cortex

Evolutionary Divergence in Developmental Strategies and Neuromodulatory Control Systems of Two Amphibian Locomotor Networks

Attempts to understand the neural mechanisms which produce behaviour must consider both prevailing sensory cues and the central cellular and synaptic changes they direct. At each level, neuromodulation can additionally shape the final output. We have investigated neuromodulation in the developing spinal motor networks in hatchling tadpoles of two closely related amphibians, Xenopus laevis and Rana temporaria to examine the subtle differences in their behaviours that could be attributed to their evolutionary divergence. At the point of hatching, both species can swim in response to a mechanosensory stimulus, however Rana embryos often display a more forceful, non-locomotory coiling behaviour. Whilst the synaptic drive that underlies these behaviours appears similar, subtle inter-specific differences in neuronal properties shape motor outputs in different ways. For example, Rana neurons express N-methyl-D-aspartate (NMDA)/serotonin (5-HT)-dependent oscillations, not present in hatchling Xenopus and many also exhibit a prominent slow spike after-hyperpolarisation. Such properties may endow the spinal circuitry of Rana with the ability to produce a more flexible range of outputs. Finally, we compare the roles of the neuromodulators 5-HT, noradrenaline (NA) and nitric oxide (NO) in shaping motor outputs. 5-HT increases burst durations during swimming in both Xenopus and Rana, but 5-HT dramatically slows the cycle period in Rana with little effect in Xenopus. Three distinct, but presumably homologous NO-containing brainstem clusters of neurons have been described, yet the effects of NO differ between species. In Xenopus, NO slows and shortens swimming in a manner similar to NA, yet in Rana NO and NA elicit the non-rhythmic coiling pattern

Methylphenidate and Atomoxetine Enhance Sensory-Evoked Neuronal Activity in the Visual Thalamus of Male Rats

Attention deficits and inappropriate regulation of sensory signal processing are hallmarks of many neuropsychiatric conditions, including attention deficit hyperactivity disorder (ADHD), for which methylphenidate (MPH) and atomoxetine (ATX) are commonly prescribed therapeutic treatments. Despite their widespread use and known mechanism of blocking reuptake of catecholamine transmitters in the brain, the resultant actions on individual neuron and neural circuit function that lead to therapeutic efficacy are poorly understood. Given the ability of MPH and ATX to improve cognitive performance in humans and rodent assays of attention, we were interested in their influence on early sensory processing in the dorsal lateral geniculate nucleus (dLGN), the primary thalamic relay for visual information from the retina to the visual cortex. In male rats, dLGN neuronal responses to light stimuli were altered in multiple ways following doses of MPH or ATX observed to enhance performance in visually-guided assays of attention in rats (MPH, 2 mg/kg; ATX, 0.5 mg/kg). Latencies to response onset and to the peak of the primary response were decreased, while the peak intensity and area of the primary response were increased. In addition, some cells that were unresponsive to light stimuli prior to drug treatment displayed a ‘gating effect,’ wherein prominent responses to light stimuli were evident following drug administration. Our results begin to reveal unique effects of MPH and ATX in enhancing sensory signal transmission through visual circuitry, and may yield new insights for understanding the pathophysiology of certain cognitive disorders and inform development of improved therapeutic treatments for these conditions

In Vitro, In Vivo, and In Silico Studies of Reticulospinal Circuits and Generalized Arousal

Generalized arousal (GA) is a fundamental force in the nervous system that alerts an individual to abrupt changes in its environment. A state of high GA is operationally defined by increases in an animal’s a.) locomotor output, b.) responsiveness to sensory stimuli, and c.) emotional reactivity. Previous studies have identified the nucleus gigantocellularis (NGC), a small group of large-bodied neurons in the hindbrain reticular formation, as a potential neuronal substrate for GA. These neurons are responsive to a wide range of sensory modalities and have diverse projections that target both forebrain areas and motor effectors directly within the spinal cord, thereby facilitating rapid responses to sensory stimulation. Here, we used three different approaches to study the role of GA in driving and modulating mammalian motor activity: in silico modeling of GA circuits, in vitro culture of a reticulospinal circuit, and in vivo behavioral assays of circadian transitions in GA. In our in silico study, we constructed a variety of computational models of the generalized arousal circuit and asked how modifying specific aspects of the NGC and its connectivity would influence the responsiveness of motor effectors in the circuit to arousing sensory stimuli. These models reveal that an NGC with a homogeneous microstructure that integrates all inputs equally and bifurcating projections that simultaneously target limbic and spinal areas is most effective at transducing an arousing sensory signal

Locus ceruleus regulates sensory encoding by neurons and networks in waking animals

Substantial evidence indicates that the locus ceruleus (LC)–norepinephrine (NE) projection system regulates behavioral state and state-dependent processing of sensory information. Tonic LC discharge (0.1–5.0 Hz) is correlated with levels of arousal and demonstrates an optimal firing rate during good performance in a sustained attention task. In addition, studies have shown that locally applied NE or LC stimulation can modulate the responsiveness of neurons, including those in the thalamus, to nonmonoaminergic synaptic inputs. Many recent investigations further indicate that within sensory relay circuits of the thalamus both general and specific features of sensory information are represented within the collective firing patterns of like-modality neurons. However, no studies have examined the impact of NE or LC output on the discharge properties of ensembles of functionally related cells in intact, conscious animals. Here, we provide evidence linking LC neuronal discharge and NE efflux with LC-mediated modulation of single-neuron and neuronal ensemble representations of sensory stimuli in the ventral posteriomedial thalamus of waking rats. As such, the current study provides evidence that output from the LC across a physiologic range modulates single thalamic neuron responsiveness to synaptic input and representation of sensory information across ensembles of thalamic neurons in a manner that is consistent with the well documented actions of LC output on cognition

Electrophysiological characterization of chronic stress-induced sensitization of noradrenergic neurons of the locus coeruleus

Chronic stress exposure can produce sensitization of norepinephrine release in the terminal fields of locus coeruleus (LC) neurons. The present studies explore the potential localization and mechanism underlying the sensitized response of LC neurons in rats following chronic exposure to cold (2 weeks; 5*C). Single unit recordings of LC neurons in halothane-anesthetized rats were used to compare the effect of intraventricular administration of corticotropin releasing hormone (CRH; 0.3-3.0µg) in control and previously cold-exposed rats. The CRH-evoked increase in LC neuron activity was enhanced following chronic cold exposure, without alteration in basal activity. The enhanced activation was only apparent at higher doses of CRH, resulting in an increased slope of the dose-response relationship for CRH in previously cold-exposed rats. It is concluded that the sensitization of CRH-evoked norepinephrine release in cold-exposed rats is accompanied by sensitization of LC neuron activity. We hypothesized that the response of LC neurons to multiple excitatory inputs is enhanced. Using in vitro intracellular recordings, we subsequently examined whether CRH exerts a direct effect on LC neurons, and which ionic currents and second messenger systems are likely affected by CRH. It was demonstrated that CRH dose-dependently increases the firing rate of LC neurons through a direct (TTX-insensitive) mechanism by decreasing a potassium conductance via adenylate cyclase and protein kinase A. The CRH-evoked activation of LC neurons is, at least in part, mediated by CRH1 receptors. In subsequent in vitro experiments using intracellular recordings, the electrophysiological properties of LC neurons were compared between control and cold-exposed rats. We observed that the excitability and input resistance of LC neurons was enhanced in slices from cold-exposed rats. In addition, the accommodation of spike firing was reduced and there was a strong trend toward a reduction of the post-activation inhibitory period. These data demonstrate that the stress-induced sensitization of LC neurons is, at least in part, maintained in vitro and suggest that alterations in electrophysiological properties of LC neurons contribute to the chronic stress-induced sensitization of central noradrenergic function observed in vivo. Furthermore, these data suggest that an alteration in auto-inhibitory control of LC activity is involved in chronic stress-induced alterations

Estimates of persistent inward current in human motor neurons during postural sway

Persistent inward current (PIC) is a membrane property critical for increasing gain of motor neuron output. In humans, most estimates of PIC are made from plantarflexor or dorsiflexor motor units with the participant in a seated position with the knee flexed. This seated and static posture neglects the task-dependent nature of the monoaminergic drive that modulates PIC activation. Seated estimates may drastically underestimate the amount of PIC that occurs in human motor neurons during functional movement. The current study estimated PIC using the conventional paired motor unit technique which uses the difference between reference unit firing frequency at test unit recruitment and reference unit firing frequency at test unit de-recruitment (∆F) during triangular-shaped, isometric ramps in plantarflexion force as an estimate of PIC. Estimates of PIC were also made during standing anterior postural sway, a postural task that elicits a ramped increase and decrease in soleus motor unit activation similar to the conventional seated ramp contractions. For each motor unit pair, ∆F estimates of PIC made during conventional isometric ramps in the seated posture were compared to those made during standing postural sway. Baseline reciprocal inhibition (RI) was also measured in each posture using the post-stimulus time histogram (PSTH) technique. Hyperpolarizing input has been shown to have a reciprocal relationship with PIC in seated posture and RI was measured to examine if the same reciprocal relationship holds true during functional PIC estimation. It was hypothesized that an increase in ∆F would be seen during standing compared to sitting due to greater neuromodulatory input. We found that ∆F estimates during standing postural sway were equal (2.44 ± 1.17, p=0.44) to those in seated PIC estimates (2.73± 1.20) using the same motor unit pair. Reciprocal inhibition was significantly lower when measured in a standing posture (0.0031 ± 0.0251,