1Copyright © 2014 Elsevier Inc. All rights reserved.

Chapter 28

Neuronal Network Plasticity and Network Interactions are Critically

Dependent on Conditional Multireceptive (CMR) Brain Regions

Carl L. Faingold, Awais Riaz, James D. Stittsworth Jr.

2Copyright © 2014 Elsevier Inc. All rights reserved.

FIGURE 28.1 Input–output relationships of a prototypical conditional multireceptive (CMR) brain region, which is capable of a significant degree of self-organization, as shown by the paired semicircular arrows. This diagram illustrates the numerous inputs that the neurons in this CMR region receive from primary networks and other CMR networks. The output of neurons in the CMR nuclei is highly dependent on the conditions that the animal is experiencing, including salient, exigent, and repetitive conditions, and can also be governed by the animal's state of vigilance as well as centrally acting pharmacological agents. The output of CMR regions is subject to nonlinearity wherein CMR neuronal responsiveness to any input can change dramatically from nonresponsiveness to hyperresponsiveness, depending on the stimulus parameter type, strength, and repetition rate, as illustrated in the graph on the right. Under nonexigent (resting) conditions, many CMR neurons exhibit negative (−) nonlinearity with minimal responsiveness or even nonresponsiveness to the input, as seen in neurons that exhibit response habituation. The various exigent conditions can cause CMR neurons to exhibit hyperresponsiveness and exhibit positive (+) nonlinearity, which can result in massive output, activating the self-organization characteristics of the CMR network, and result in emergent properties of that network that range, for example, from startle responses to generalized seizures. CMR neurons that exhibit negative nonlinearity under resting conditions can convert to positive nonlinearity in response to exigent changes in the animal's behavioral state (dotted line). The nonlinear output characteristics of CMR brain regions contrast with the relatively linear responses seen in primary networks, such as sensory systems.

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FIGURE 28.2 Top panel: Typical example of the BRF (pontine) neuronal response attenuation (habituation) produced by increasing the repetition rate of an acoustic stimulus (100 ms, 12 kHz tone burst) in a normal (Sprague–Dawley) awake, behaving rat. The BRF neuronal firing was decreased to less than 50% of the 0.5 Hz rate (closed circles) at both 1 Hz (open circles) and 2 Hz (square symbols). Bottom panels: Example of enhanced responsiveness induced by a GABAA receptor antagonist (bemegride, or BMG) in a CMR neuron in BRF at habituating versus nonhabituating rates of stimulus presentation. This figure shows the effects of bemegride on the responses to auditory stimuli (click, 95 dB (SPL), 25 presentations at (A–C) 2 Hz and (D–F) 0.5 Hz). The middle graph shows total action potentials per poststimulus time histogram (PSTH) as a percentage of predrug control for each of the two repetition rates. The PSTH is a summation of single neuron extracellular action potential in response to a constant number of repetitions, which are shown in the bottom panel. The letters on the PSTHs correspond to the points on the time course graphs in the middle panel. In the control column in the middle panel, this neuron responded well to the auditory stimulus at the 0.5 Hz repetition rate (D), as indicated by the consistent time-locked peak in the PSTH, but relatively little response was evoked at 2 Hz in control (A), which shows repetition-induced response attenuation (“habituation”). After BMG (1.8 mg/kg, intravenous) (see the “Bemegride” column), the number of action potentials in the PSTH is enhanced to a maximum of 390% of control levels at 2 Hz (B), while at 0.5 Hz the percentage increase is ∼

100%. Recovery to near-control values is noted at 3 min following termination of BMG administration at 2 Hz and at about 14 min at ∼0.5 Hz (C). (Source: From Reference 56 with permission.) Stimulus onset is at 0 ms in each PSTH (PSTH parameters: 25 stimulus presentations, 1 ms bin width). Top-panel data were obtained with microwire electrodes in awake, behaving rats, and data in the lower panels were obtained from an unanesthetized cat with a glass microelectrode. N is the total number of action potentials in each PSTH.

(Source: Modified from References 17,56 with permission.)

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FIGURE 28.3 Diagram of the network that mediates the initial and shortest latency component of the acoustic startle response. The intense and unexpected acoustic stimulus is delivered to the ear and is transmitted via the cochlea to the primary auditory network, beginning with the cochlear nucleus, which projects to the superior olivary complex (C). Both of these primary auditory structures project to the brainstem (ponto-medullary) reticular formation, which projects via the reticulospinal tract to the spinal cord. This pathway produces the short-latency motor component of the startle response.

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FIGURE 28.4 CNS depressant drugs, such as barbiturates, reduce CMR neuronal firing in the ventrolateral periaqueductal gray (PAG) at low doses. (A) The mean (±SEM) reduction of both spontaneous and thermally evoked firing by pentobarbital (N = 18 neurons) at 15 min after systemic (intraperitoneal, or i.p.) administration, with recovery by 30 min. (B–D) An example rate meter histogram analysis of a PAG neuronal spontaneous and evoked excitatory firing in response to a 30 s (bracket) noxious thermal stimulation (53 °C) before (B, “Control”), 15 min after pentobarbital (15 mg/kg i.p.) treatment (C, “Drug”), and during the subsequent recovery (at 30 min) (D, “Recovery”). Prior to pentobarbital, the majority (18/35) of PAG neurons increased firing in response to the thermal stimulus in this study. (Note that 10 mg/kg of pentobarbital had no significant effect on PAG neuronal firing, while 20 mg/kg produced greater depression of PAG firing than the 15 mg dose.) The action potential above the top histogram represents the waveform of the neuron being analyzed. The onset and duration of the thermal stimulus (Stim.) are illustrated by the bracket. Data from awake, behaving normal (Sprague–Dawley) rat. Significance at ∗ p < 0.01 (repeated-measure ANOVA).

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FIGURE 28.5 Induction of responsiveness in CMR neurons by GABAA receptor antagonists to stimuli in several stimulus modalities. This figure shows examples of brainstem (mesencephalic) reticular formation (BRF) neurons that were minimally responsive to stimuli before drug administration (“Control” column). However, after administration of GABAA antagonists, each of these neurons became responsive to the stimuli (“Drug” column) and recovered with time (“Recovery” column). (A) An example of poststimulus time histograms (PSTHs) of a BRF neuronal response to visual stimuli (duration: a 10 μs flash) and the response increase after administration of the GABAA antagonist pentylenetetrazol (PTZ, 12.5 mg/kg, i.v.). The photographs above each PSTH in line (A) illustrate three examples of the oscilloscope traces of action potentials from which the PSTH was constructed. (B) A different BRF neuronal response to auditory stimuli (95 dB clicks SPL) and the insets above each PSTH shows the PSTH of responses of the same neuron to visual stimuli. (C) The response of the same neuron in (B) to electrical stimuli (0.1 ms) in the primary auditory network (lateral lemniscus). This neuron became responsive to all three stimuli simultaneously following PTZ (7.5 mg/kg, i.v.). (D) An example of the effect of the GABAA antagonist, bicuculline, applied by iontophoresis (80 nA for 3 min) in another BRF neuron, which also induced a significant increase in responsiveness in this neuron. This effect was observed in unanesthetized cats (lines A–C) and rat (line D) (PSTH parameters: 50 stimulus presentations, 1 ms bin width, 0.5 Hz rate). N is the total number of action potentials in each PSTH. (Stimulus onset is at 0 ms in each PSTH.)

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FIGURE 28.6 Effects of a GABAA antagonist on the responsiveness of CMR neurons in the BRF as compared to primary sensory neurons. This figure illustrates an example of the effects of the GABAA antagonist, pentylenetetrazol (PTZ), on the responses to auditory stimuli of primary auditory (inferior colliculus, or IC) and brainstem (mesencephalic) reticular formation (BRF). The bar graphs in panel A show the mean response increase from control (predrug) for each brain site, which was >300% in BRF neurons and 60% in IC neurons ∼in this series of studies. An example of the comparative effect on BRF neuronal response is shown by the poststimulus time histograms (PSTHs) in panel B, while the simultaneously recorded IC neuronal response is shown by the PSTHs in panel C. The control columns in panels B and C illustrate the responses of both neurons to the acoustic stimulus (prior to drug administration). The IC neuron was quite responsive, as shown by the consistent time-locked response (peak in the PSTH), while the BRF neuron was not clearly responsive. Following administration of PTZ (6 mg/kg, i.v.) (see the “Drug” column), the BRF neurons became very responsive to the stimulus, indicated by the emerging peak in the PSTH. At the same time, the IC neuron showed a minor firing increase. Recovery toward control firing patterns occurred in both neurons several minutes later (“Recovery” column). Increases greater than 10% were seen in 51% of IC neurons and 85% of BRF neurons in the same experimental series. Stimuli: 95 dB SPL re 0.002 dyne/cm2, 0.1 ms clicks with onset at 0 time on each PSTH; PSTH parameters: 50 stimulus presentations, 1 ms bin width, 0.5 Hz rate. Data obtained from an unanesthetized cat with glass microelectrodes. N is the total number of action potentials in each PSTH.

(Source: Modified from Reference 114 with permission.)

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FIGURE 28.7 Effects of increasing the intensity of electrical stimulus in the central nucleus of amygdala on the mean evoked single-unit action potentials (APs) per histogram (post stimulus-time histogram, or PSTH) recorded from the ventrolateral periaqueductal gray (PAG) in AGS-kindled GEPR-9s (n = 7 neurons in five rats) (dark bars) as compared with nonkindled GEPR-9s (n = 5 neurons in three rats) (lighter bars). There were significant intensity-related firing increases in both groups of rats. The mean differences in the AGS-kindled GEPR-9s, as compared to nonkindled GEPR-9s, were significantly greater and began at a lower stimulus intensity (150 μA) in AGS-kindled rats. The electrical stimulus artifact was seen between 0 and 3 ms, and the evoked single-unit responses appeared within 25 ms following the electrical stimulus. Therefore, the mean of APs and PSTH appearing between 4 and 25 ms of the PSTHs are shown. Statistical comparisons between groups were done using univariate ANOVA followed by independent sample t-tests for each electrical stimulus intensity (∗p < 0.05), and within-group comparisons were done using one-way ANOVA followed by Tukey HSD (#p < 0.001; ∗∗p < 0.01; ∗p < 0.05 (Source: From Reference 161, with permission.)) in awake, behaving epileptic rats (GEPR-9) with microwire electrodes.