Entanglement between Thermoregulation and Nociception in the rat: The case of Morphine

In thermal neutral condition, rats display cyclic variations of the vasomotion of the tail and paws, the most widely used target organs in current acute or chronic animal models of pain. Systemic morphine elicits their vasoconstriction followed by hyperthermia in a naloxone-reversible and dose-dependant fashion. The dose-response curves were steep with ED50 in the 0.5-1 mg/kg range. Given the pivotal functional role of Rostral Ventro-medial Medulla (RVM) in nociception and rostral Medullary Raphe (rMR) in thermoregulation, two largely overlapping brain regions, the RVM/rMR was blocked by muscimol: it suppressed the effects of morphine. "On-" and "Off" neurons recorded in RVM/rMR are activated and inhibited by thermal nociceptive stimuli, respectively. They are also implicated in regulating the cyclic variations of the vasomotion of the tail and paws seen in thermal neutral condition. Morphine elicited abrupt inhibition and activation of the firing of On- and Off-cells recorded in the RVM/rMR. By using a model that takes into account the power of the radiant heat source, the initial skin temperature, the core body temperature and the peripheral nerve conduction distance, one can argue that the morphine-induced increase of reaction time is mainly related to the morphine-induced vasoconstriction. This statement was confirmed by analyzing in psychophysical terms the tail-flick response to random variations of noxious radiant heat. Although the increase of a reaction time to radiant heat is generally interpreted in terms of analgesia, the present data question the validity of using such an approach to build a pain index.

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Glycolysis selectively shapes the presynaptic action potential waveform

Mitochondria are major suppliers of cellular energy in neurons; however, utilization of energy from glycolysis versus mitochondrial oxidative phosphorylation (OxPhos) in the presynaptic compartment during neurotransmission is largely unknown. Using presynaptic and postsynaptic recordings from the mouse calyx of Held, we examined the effect of acute selective pharmacological inhibition of glycolysis or mitochondrial OxPhos on multiple mechanisms regulating presynaptic function. Inhibition of glycolysis via glucose depletion and Iodoacetic Acid (IAA, 1mM) treatment, but not mitochondrial OxPhos, rapidly altered transmission, resulting in highly variable, oscillating responses. At reduced temperature, this same treatment attenuated synaptic transmission, due to a smaller and broader presynaptic AP waveform. We show via experimental manipulation and ion channel modeling that the altered AP waveform results in smaller Ca²⁺-influx, resulting in attenuated excitatory postsynaptic currents (EPSCs). In contrast, inhibition of mitochondria-derived ATP production via extracellular pyruvate depletion and bath-applied oligomycin (1 µM) had no significant effect on Ca²⁺-influx, did not alter the AP waveform within the same time frame (up to 30 min), and the resultant EPSC remained unaffected. Glycolysis, but not mitochondrial OxPhos, is thus required to maintain basal synaptic transmission at the presynaptic terminal. We propose that glycolytic enzymes are closely apposed to ATP-dependent ion pumps on the presynaptic membrane. Our results indicate a novel mechanism for the effect of hypoglycemia on neurotransmission. Attenuated transmission likely results from a single presynaptic mechanism at reduced temperature: a slower, smaller AP, prior to and independent of any effect on synaptic vesicle release or receptor activity.

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Normal Correspondence of Tectal Maps for Saccadic Eye Movements in Strabismus

The superior colliculus is a major brainstem structure for the production of saccadic eye movements. Electrical stimulation at any given point in the motor map generates saccades of defined amplitude and direction. It is unknown how this saccade map is affected by strabismus. Three macaques were raised with exotropia, an outwards ocular deviation, by detaching the medial rectus tendon in each eye at age one month. The animals were able to make saccades to targets with either eye and appeared to alternate fixation freely. To probe the organization of the superior colliculus, microstimulation was applied at multiple sites, with the animals either free-viewing or fixating a target. On average, microstimulation drove nearly conjugate saccades, similar in both amplitude and direction, but separated by the ocular deviation. Two monkeys showed a pattern deviation, characterized by a systematic change in the relative position of the two eyes with certain changes in gaze angle. These animals' saccades were slightly different for the right eye and left eye in their amplitude or direction. The differences were consistent with the animals' underlying pattern deviation, measured during static fixation and smooth pursuit. The tectal map for saccade generation appears to be normal in strabismus, but saccades may be affected by changes in the strabismic deviation that occur with different gaze angles. -

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Maximal intermittent contractions of the first dorsal interosseous inhibits voluntary activation of the contralateral homologous muscle

The aim of this study was to investigate how maximal intermittent contractions for a hand muscle influence cortical and reflex activity, as well as the ability to voluntarily activate, the homologous muscle in the opposite limb. Twelve healthy subjects (age: 24 ± 3 years, all right hand dominant) performed maximal contractions of the dominant limb first dorsal interosseous (FDI), and activity of the contralateral FDI was examined in a series of experiments. Index finger abduction force, FDI EMG, motor evoked potentials and heteronomous reflexes were obtained from the contralateral limb during brief non-fatiguing contractions. The same measures, as well as the ability to voluntarily activate the contralateral FDI, were then assessed in an extended intermittent contraction protocol that elicited fatigue. Brief contractions under non-fatigued conditions increased index finger abduction force, FDI EMG, and motor evoked potential amplitude of the contralateral limb. However, when intermittent maximal contractions were continued until fatigue, there was an inability to produce maximal force with the contralateral limb (~30%) which was coupled to a decrease in the level of voluntary activation (~20%). These declines were present without changes in reflex activity, and regardless of whether cortical or motor point stimulation was used to assess voluntary activation. It is concluded that performing maximal intermittent contractions with a single limb causes an inability of the CNS to maximally drive the homologous muscle of the contralateral limb. This was, in part, mediated by mechanisms that involve the motor cortex ipsilateral to the contracting limb.

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High frequency neural activity predicts word parsing in ambiguous speech streams

During speech listening, the brain parses a continuous acoustic stream of information into computational units (e.g. syllables or words) necessary for speech comprehension. Recent neuroscientific hypotheses propose that neural oscillations contribute to speech parsing, but whether they do so on the basis of acoustic cues (bottom-up acoustic parsing) or as a function of available linguistic representations (top-down linguistic parsing) is unknown. In this magnetoencephalography study, we contrasted acoustic and linguistic parsing using bistable speech sequences. While listening to the speech sequences, participants were asked to maintain one of the two possible speech percepts through volitional control. We predicted that the tracking of speech dynamics by neural oscillations would not only follow the acoustic properties but also shift in time according to the participant's conscious speech percept. Our results show that the latency of high-frequency activity (specifically, beta and gamma bands) varied as a function of the perceptual report. In contrast, the phase of low-frequency oscillations was not strongly affected by top-down control. While changes in low-frequency neural oscillations were compatible with the encoding of pre-lexical segmentation cues, high-frequency activity specifically informed on an individual's conscious speech percept.

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Effect of informational content of noise on speech representation in the aging midbrain and cortex

The ability to understand speech is significantly degraded by aging, particularly in noisy environments. One way that older adults cope with this hearing difficulty is through the use of contextual cues. Several behavioral studies have shown that older adults are better at following a conversation when the target speech signal has high contextual content or when the background distractor is not meaningful. Specifically, older adults gain significant benefit in focusing on and understanding speech if the background is spoken by a talker in a language that is not comprehensible to them (i.e. a foreign language). To better understand the neural mechanisms underlying this benefit in older adults, we investigated aging effects on midbrain and cortical encoding of speech when in the presence of a single competing talker speaking in language that is meaningful or meaningless to the listener (i.e., English vs. Dutch). Our results suggest that neural processing is strongly affected by the informational content of noise. Specifically, older listeners' cortical responses to the attended speech signal are less deteriorated when the competing speech signal is an incomprehensible language than when it is their native language. Conversely, temporal processing in the midbrain is affected by different backgrounds only during rapid changes in speech, and only in younger listeners. Additionally, we found that cognitive decline is associated with an increase in cortical envelope tracking, suggesting an age-related over (or inefficient) use of cognitive resources that may explain their difficulty in processing speech targets while trying to ignore interfering noise.

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Dynamic Balance of Excitation and Inhibition Rapidly Modulates Spike Probability and Precision in Feed-Forward Hippocampal Circuits

Feed-forward inhibitory (FFI) circuits are important for many information-processing functions. FFI circuit operations critically depend on the balance and timing between the excitatory and inhibitory components, which undergo rapid dynamic changes during neural activity due to short-term plasticity (STP) of both components. How dynamic changes in excitation/inhibition (E/I) balance during spike trains influence FFI circuit operations remains poorly understood. Here we examined the role of STP in the FFI circuit functions in the mouse hippocampus. Using a coincidence detection paradigm with simultaneous activation of two Schaffer collateral inputs, we found that the spiking probability in the target CA1 neuron was increased while spike precision concomitantly decreased during high-frequency bursts compared to a single spike. Blocking inhibitory synaptic transmission revealed that dynamics of inhibition predominately modulates the spike precision but not the changes in spiking probability, while the latter is modulated by the dynamics of excitation. Further analyses combining whole-cell recordings and simulations of the FFI circuit suggested that dynamics of the inhibitory circuit component may influence spiking behavior during bursts by broadening the width of excitatory postsynaptic responses and that the strength of this modulation depends on the basal E/I ratio. We verified these predictions using a mouse model of Fragile X Syndrome, which has an elevated E/I ratio, and found a strongly reduced modulation of postsynaptic response width during bursts. Our results suggest that changes in the dynamics of excitatory and inhibitory circuit components due to STP play important yet distinct roles in modulating the properties of FFI circuits.

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