Circadian variability of body temperature responses to methamphetamine

Vital parameters of living organisms exhibit circadian rhythmicity. Although rats are nocturnal animals, most of the studies involving rats are performed during the day. The objective of this study was to examine the circadian variability of the body temperature responses to methamphetamine. Body temperature was recorded in male Sprague-Dawley rats that received intraperitoneal injections of methamphetamine (Meth, 1 or 5 mg/kg) or saline at 10 AM or at 10 PM. The baseline body temperature at night was 0.8°C higher than during the day. Both during the day and at night, 1 mg/kg of Meth induced monophasic hyperthermia. However, the maximal temperature increase at night was 50% smaller than during the daytime. Injection of 5 mg/kg of Meth during the daytime caused a delayed hyperthermic response. In contrast, the same dose at night produced responses with a tendency toward a decrease of body temperature. Using mathematical modeling, we previously showed that the complex dose dependence of the daytime temperature responses to Meth results from an interplay between inhibitory and excitatory drives. In this study, using our model, we explain the suppression of the hyperthermia in response to Meth at night. First, we found that the baseline activity of the excitatory drive is greater at night. It appears partially saturated and thus is additionally activated by Meth to a lesser extent. Therefore, the excitatory component causes less hyperthermia or becomes overpowered by the inhibitory drive in response to the higher dose. Second, at night the injection of Meth results in reduction of the equilibrium body temperature, leading to gradual cooling counteracting hyperthermia.

Behavioral Time Course of Microstimulation in Cortical Area MT

Electrical stimulation of the brain is a valuable research tool and has shown therapeutic promise in the development of new sensory neural prosthetics. Despite its widespread use, we still do not fully understand how current passed through a microelectrode interacts with functioning neural circuits. Past behavioral studies have suggested that weak electrical stimulation (referred to as microstimulation) of sensory areas of cortex produces percepts that are similar to those generated by normal sensory stimuli. In contrast, electrophysiological studies using in vitro or anesthetized preparations have shown that neural activity produced by brief microstimulation is radically different and longer lasting than normal responses. To help reconcile these two aspects of microstimulation, we examined the temporal properties that microstimulation has on visual perception. We found that brief application of subthreshold microstimulation in the middle temporal (MT) area of visual cortex produced smaller and longer-lasting effects on motion perception compared with an equivalent visual stimulus. In agreement with past electrophysiological studies, a computer simulation reproduced our behavioral effects when the time course of a single microstimulation pulse was modeled with three components: an immediate fast strong excitatory component, followed by a weaker inhibitory component, and then followed by a long duration weak excitatory component. Overall, these results suggest the behavioral effects of microstimulation in our experiments were caused by the unique and long-lasting temporal effects microstimulation has on functioning cortical circuits.

Presynaptic actions of endocannabinoids mediate α-MSH-induced inhibition of oxytocin cells

We recently showed that central injections of α-melanocyte-stimulating hormone (α-MSH) inhibits oxytocin cells and reduces peripheral release of oxytocin, but induces oxytocin release from dendrites. Dendritic oxytocin release can be triggered by agents that mobilize intracellular calcium. Oxytocin, like α-MSH, mobilizes intracellular calcium stores in oxytocin cells and triggers presynaptic inhibition of afferent inputs that is mediated by cannabinoids. We hypothesized that this mechanism might underlie the inhibitory effects of α-MSH. To test this, we recorded extracellularly from identified oxytocin and vasopressin cells in the anesthetized rat supraoptic nucleus (SON). Retrodialysis of a CB1 cannabinoid receptor antagonist to the SON blocked the inhibitory effects of intracerebroventricular injections of α-MSH on the spontaneous activity of oxytocin cells. We then monitored synaptically mediated responses of SON cells to stimulation of the organum vasculosum of the lamina terminalis (OVLT); this evoked a mixed response comprising an inhibitory component mediated by GABA and an excitatory component mediated by glutamate, as identified by the effects of bicuculline and 6-cyano-7-nitroquinoxaline-2,3-dione applied to the SON by retrodialysis. Application of CB1 receptor agonists to the SON attenuated the excitatory effects of OVLT stimulation in both oxytocin and vasopressin cells, whereas α-MSH attenuated the responses of oxytocin cells only. Thus α-MSH can act as a “switch”; it triggers oxytocin release centrally, but at the same time through initiating endocannabinoid production in oxytocin cells inhibits their electrical activity and hence, peripheral secretion.

Nonlinear Encoding of Tactile Patterns in the Barrel Cortex

Cells in the rodent barrel cortex respond to vibrissa deflection with a brief excitatory component and a longer suppressive component. The response to a given deflection is thus scaled because of suppression induced by a preceding deflection, causing the neuronal response to be linked to the temporal properties of the peripheral stimulus. A paired-deflection stimulus was used to characterize the postexcitatory suppression and a 3-deflection stimulus was used to investigate the nonlinear response to patterns of whisker deflections in barbiturate-anesthetized Sprague–Dawley rats. The postexcitatory suppression was not dependent on a sensory-evoked action potential to the first deflection, implying that it is likely a subthreshold property of the network. The suppression induced by a deflection served to suppress both the excitatory and suppressive components of a subsequent neuronal response, thus effectively disinhibiting it. Two different response properties were observed in the recorded cells. Approximately 65% responded to a vibrissa deflection with an excitatory component followed by a suppressive component and 35% responded with excitation, suppression, and a subsequent rebound in excitation. Based on these observations of postexcitatory dynamics, a prediction method was used to estimate neuronal responses to more complex stimulus trains. Using the 2nd-order representation obtained from the paired-deflection stimulus, responses to general periodic deflection patterns were well predicted. A higher cutoff frequency was predicted for rebound cells compared with cells not exhibiting rebound excitation, consistent with experimental observations. The method also predicted the response of neurons to a random aperiodic deflection pattern. Therefore the temporal structure of cortical dynamics after a single deflection dictates the response to complex temporal patterns, which are more representative of stimuli encountered under natural conditions.

A Temporal Dissociation of Subliminal versus Supraliminal Fear Perception: An Event-related Potential Study

Current theories of emotion suggest that threat-related stimuli are first processed via an automatically engaged neural mechanism, which occurs outside conscious awareness. This mechanism operates in conjunction with a slower and more comprehensive process that allows a detailed evaluation of the potentially harmful stimulus (LeDoux, 1998). We drew on the Halgren and Marinkovic (1995) model to examine these processes using event-related potentials (ERPs) within a backward masking paradigm. Stimuli used were faces with fear and neutral (as baseline control) expressions, presented above (supraliminal) and below (subliminal) the threshold for conscious detection. ERP data revealed a double dissociation for the supraliminal versus subliminal perception of fear. In the subliminal condition, responses to the perception of fear stimuli were enhanced relative to neutral for the N2 “excitatory” component, which is thought to represent orienting and automatic aspects of face processing. By contrast, supraliminal perception of fear was associated with relatively enhanced responses for the late P3 “inhibitory” component, implicated in the integration of emotional processes. These findings provide evidence in support of Halgren and Marinkovic's temporal model of emotion processing, and indicate that the neural mechanisms for appraising signals of threat may be initiated, not only automatically, but also without the need for conscious detection of these signals.

Activation and Reconfiguration of Fictive Feeding by the OctopamineContaining Modulatory OC Interneurons in the SnailLymnaea

We describe the role of the octopamine-containing OC interneurons in the buccal feeding system of Lymnaea stagnalis. OC neurons are swallowing phase interneurons receiving inhibitory inputs in the N1 and N2 phases, and excitatory inputs in the N3 phase of fictive feeding. Although the OC neurons do not always fire during feeding, the feeding rate is significantly ( P < 0.001) higher when both SO and OC fire in each cycle than when only the SO fires. In 28% of silent preparations, a single stimulation of an OC interneuron evokes the feeding pattern. Repetitive stimulation of the OC interneuron increases the proportion of responsive preparations to 41%. The OC interneuron not only changes both the feeding rate and reconfigures the pattern. Depolarization of the OC interneurons increases the feeding rate and removes the B3 motor neuron from the firing sequence. Hyperpolarization slows it down (increasing the duration of N1 and N3 phases) and recruits the B3 motor neuron. OC interneurons form synaptic connections onto buccal motor neurons and interneurons but not onto the cerebral (cerebral giant cell) modulatory neurons. OC interneurons are electrically coupled to all N3 phase (B4, B4Cl, B8) feeding motor neurons. They form symmetrical connections with the N3p interneurons having dual electrical (excitatory) and chemical (inhibitory) components. OC interneurons evoke biphasic synaptic inputs on the protraction phase interneurons (SO, N1L, N1M), with a short inhibition followed by a longer lasting depolarization. N2d interneurons are hyperpolarized, while N2v interneurons are slowly depolarized and often fire a burst after OC stimulation. Most motor neurons also receive synaptic responses from the OC interneurons. Although OC and N3p interneurons are both swallowing phase interneurons, their synaptic contacts onto follower neurons are usually different (e.g., the B3 motor neurons are inhibited by OC, but excited by N3p interneurons). Repetitive stimulation of OC interneuron facilitates the excitatory component of the biphasic responses evoked on the SO, N1L, and N1M interneurons, but neither the N2 nor the N3 phase interneurons display a similar longer-lasting excitatory effect. OC interneurons are inhibited by all the buccal feeding interneurons, but excited by the serotonergic modulatory CGC neurons. We conclude that OC interneurons are a new kind of swallowing phase interneurons. Their connections with the buccal feeding interneurons can account for their modulatory effects on the feeding rhythm. As they contain octopamine, this is the first example in Lymnaea that monoaminergic modulation and reconfiguration are provided by an intrinsic member of the buccal feeding network.

Mechanosensory Modulation of Perioral Neuronal Groups During Active Force Dynamics

The spatiotemporal organization of the mechanically evoked perioral sensorimotor response was sampled from five normal females using a custom-designed linear motor operating under force feedback. Electromyographic activity was sampled from the superior and inferior segments of the orbicularis oris muscle during the production of a visually guided ramp-and-hold lip-rounding task. Brief mechanical inputs of approximately 0.45 N delivered to the left upper lip during the ramp-and-hold task produced a composite myogenic response characterized by phases of excitation and suppression. Modulation of the primary excitatory component (R1) of the mechanically evoked perioral response was found to be highly dependent upon the rate of force recruitment (1 N/s vs. 4 N/s) and the phase of force recruitment (20% vs. 50% vs. 80% of 1 N end-point force). Modulation of later occurring inhibitory (S1) and excitatory (R2) potentials were also found to be dependent upon differences in the rate and phase of force recruitment. The organization of the perioral sensorimotor response is considered in relation to speech motor control and the dynamic organization of neuronal groups subserving perioral sensorimotor activity.

Somatosensory cortical efferent neurons of the awake rabbit: latencies to activation via supra--and subthreshold receptive fields

1. Latencies to peripheral sensory stimulation were examined in four classes of antidromically identified efferent neurons in the primary somatosensory cortex (S1) of awake rabbits. Both suprathreshold responses (action potentials) and subthreshold responses were examined. Subthreshold responses were examined by monitoring the thresholds of efferent neurons to juxtasomal current pulses (JSCPs) delivered through the recording microelectrode (usually 1-3 microA). Through the use of this method, excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) were manifested as decreases and increases in threshold, respectively. Efferent populations examined included callosal (CC) neurons, ipsilateral corticocortical (C-IC) neurons, and descending corticofugal neurons of layer 5 (CF-5) and layer 6 (CF-6). Very brief air puffs (rise and fall times 0.6 ms) were delivered to the receptor periphery via a high-speed solenoid valve. 2. Whereas all CF-5 neurons had demonstrable suprathreshold excitatory and/or inhibitory responses to peripheral stimulation, most CC, C-IC, and CF-6 neurons did not. CC and CF-6 neurons that yielded no suprathreshold response to the stimulus had lower axonal conduction velocities than those that did respond (P < 0.0001 in both cases). However, subthreshold receptive fields could be demonstrated in many of the otherwise unresponsive CC (81%), C-IC (88%), and CF-6 (43%) neurons. The subthreshold responses usually consisted of an initial excitatory component (a decrease in the threshold to the JSCP) and a subsequent long-duration (> 80 ms) inhibitory component. A few neurons (1 CC, 1 C-IC, and 5 CF-6) showed an initial short latency inhibitory response in the absence of any excitatory component. 3. Some CC and C-IC neurons yielded supra- and/or subthreshold responses to peripheral stimulation at latencies of 6.1-7 ms. All such neurons were found at intermediate cortical depths (thought to correspond to deep layer 2-3 through layer 5). It is argued that such latencies are indicative of monosynaptic activation via thalamic afferents. Very superficial CC and C-IC neurons, and all CF-6 neurons responded to latencies of > 7 ms. All CF-5 neurons responded to latencies of > 8 ms, although many were found at the same depth as the deeper CC and C-IC neurons that responded at monosynaptic latencies. These results indicate that cortical cell type as well as laminar position are important factors that determine the sequence of intracortical neuronal activation after peripheral sensory stimulation.

Central pattern generator interneurons are targets for the modulatory serotonergic cerebral giant cells in the feeding system of Lymnaea

1. The objective of the experiments was to explore the modulatory functions of the serotonergic cerebral giant cells (CGCs) of the Lymnaea feeding system by examining their synaptic connections with the central pattern generator (CPG) interneurons and the modulatory slow oscillator (SO) interneuron. 2. One type of modulatory function, "gating," requires that the CGCs fire tonically at a minimum of 7 spikes/min. Above this minimum level the CGCs control the frequency of CPG interneuron oscillation-- "frequency control," a second type of modulation. In an SO-driven fictive feeding rhythm, an increase in the frequency of the rhythm, with increased CGC firing rate, resulted from a reduction in the duration of the N1 (protraction) and N2 (rasp) phases of the feeding cycle with little effect on the N3 (swallow) phase. 3. The CGCs excited the N1 phase interneurons SO and N1M (N1 medial) cells but had no consistent effects on the N1 lateral cells. The CGC-->SO postsynaptic response was probably monosynaptic (< or = 200 ms in duration) with unitary 1:1 excitatory postsynaptic potentials (EPSPs) following each CGC spike. The CGC-->N1M excitatory response was slow and nonunitary, and a burst of CGC spikes evoked a depolarization of the N1M cells that lasted up to 10 s and triggered N1M cell bursts. Both CGC-->SO and CGC-->N1M excitatory responses could be mimicked by the focal application of serotonin (5-HT). 4. Both CGC-->SO and CGC-->N1M excitatory connections systematically increased the N1M cell firing rate within the CGCs' physiological firing range (0-40 spikes/min). This was due to both the direct (CGC-->N1M) and indirect (CGC-->SO-->N1M) excitatory synaptic pathways. The CGC-induced increase in N1M cell firing rate probably accounted for the reduced duration of the N1M cell feeding burst by causing a more rapid reversal of the feeding cycle from the N1 phase to the N2 phase. This phase reversal was due to the previously described recurrent inhibitory pathway (N1-->N2 excitation followed by N2-->N1 inhibition). 5. The CGCs' ability to provide a depolarizing drive to the N1M cells meant that this excitatory connection was also likely to be important for gating. 6. Activity in the CGCs produced nonunitary, long-lasting, excitatory postsynaptic responses on the N2 ventral (N2v) CPG interneurons, and these were likely to be involved in both the gating and the frequency control by the CGCs on the N2 phase of the feeding rhythm. Suppressing CGC tonic firing initially increased the duration of the N2v plateau (which determines the duration of the N2 phase of the feeding cycle, frequency function) but eventually led to a loss of N2v plateauing (gating function). 7. Nonunitary, weakly inhibitory CGC-->N2 dorsal responses were recorded that could be mimicked by the application of 5-HT. 8. Spikes in the CGCs evoked 1:1 monosynaptic EPSPs in the N3 tonic (N3t) CPG interneurons. This excitatory effect could be mimicked by the application of 5-HT. Within the physiological range of CGC firing, this excitation did not appear to influence the firing rate of the N3t cells. 9. N3 phasic (N3p) CPG interneurons showed biphasic (hyperpolarizing followed by depolarizing) unitary responses to spikes evoked in the CGCs. The inhibitory synaptic response was maintained in a high-Ca2+/high-Mg2+ (Hi-Di) saline and was mimicked by the focal application of 5-HT, indicating that it was probably monosynaptic. The excitatory component was, however, reduced in a Hi-Di saline, indicating that it was probably polysynaptic. Suppressing the CGCs during an SO-driven feeding rhythm caused the N3p cells to fire less, suggesting that the removal of the excitatory component of the response might be significant. 10. We conclude that the general depolarizing effects of the CGCs on a number of the CP