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The induction of pain: an integrative review

The principal features and mechanisms of dopamine modulation in the prefrontal cortex

The basal ganglia are a chain of subcortical nuclei that facilitate action selection. Two striatal projection systems—so-called direct and indirect pathways—form the functional backbone of the basal ganglia circuit. Twenty years ago, investigators proposed that the striatum's ability to use dopamine (DA) rise and fall to control action selection was due to the segregation of D1 and D2 DA receptors in direct- and indirect-pathway spiny projection neurons. Although this hypothesis sparked a debate, the evidence that has accumulated since then clearly supports this model. Recent advances in the means of marking neural circuits with optical or molecular reporters have revealed a clear-cut dichotomy between these two cell types at the molecular, anatomical, and physiological levels. The contrast provided by these studies has provided new insights into how the striatum responds to fluctuations in DA signaling and how diseases that alter this signaling change striatal function.

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Modulation of Striatal Projection Systems by Dopamine

Developing networks follow common rules to shift from silent cells to coactive networks that operate via thousands of synapses. This review deals with some of these rules and in particular those concerning the crucial role of the neurotransmitter gamma-aminobuytric acid (GABA), which operates primarily via chloride-permeable GABA(A) receptor channels. In all developing animal species and brain structures investigated, neurons have a higher intracellular chloride concentration at an early stage leading to an efflux of chloride and excitatory actions of GABA in immature neurons. This triggers sodium spikes, activates voltage-gated calcium channels, and acts in synergy with NMDA channels by removing the voltage-dependent magnesium block. GABA signaling is also established before glutamatergic transmission, suggesting that GABA is the principal excitatory transmitter during early development. In fact, even before synapse formation, GABA signaling can modulate the cell cycle and migration. The consequence of these rules is that developing networks generate primitive patterns of network activity, notably the giant depolarizing potentials (GDPs), largely through the excitatory actions of GABA and its synergistic interactions with glutamate signaling. These early types of network activity are likely required for neurons to fire together and thus to "wire together" so that functional units within cortical networks are formed. In addition, depolarizing GABA has a strong impact on synaptic plasticity and pathological insults, notably seizures of the immature brain. In conclusion, it is suggested that an evolutionary preserved role for excitatory GABA in immature cells provides an important mechanism in the formation of synapses and activity in neuronal networks.

GABA: A Pioneer Transmitter That Excites Immature Neurons and Generates Primitive Oscillations

D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons

The cellular and network mechanisms of the transition of brief interictal discharges to prolonged seizures are a crucial issue in epilepsy. Here we used hippocampal slices exposed to ACSF containing 0 Mg2+ to explore mechanisms for the transition to prolonged (3–42 sec) seizure-like (“ictal”) discharges. Epileptiform activity, evoked by Shaffer collateral stimulation, triggered prolonged bursts in CA1, in 50–60% of slices, from both adult and young (postnatal day 13–21) rats. In these cases the first component of the CA1 epileptiform burst was followed by a train of population spikes at frequencies in the γ band and above (30–120 Hz, reminiscent of tetanically evoked γ oscillations). The γ burst in turn could be followed by slower repetitive “tertiary” bursts. Intracellular recordings from CA1 during the γ phase revealed long depolarizations, action potentials rising from brief apparent hyperpolarizations, and a drop of input resistance. The CA1 γ rhythm was completely blocked by bicuculline (10–50 μm), by ethoxyzolamide (100 μm), and strongly attenuated in hyperosmolar perfusate (50 mm sucrose). Subsequent tertiary bursts were also blocked by bicuculline, ethoxyzolamide, and in hyperosmolar perfusate. In all these cases intracellular recordings from CA3 revealed only short depolarizations. We conclude that under epileptogenic conditions, γ band oscillations arise from GABAAergic depolarizations and that this activity may lead to the generation of ictal discharges.

https://www.jneurosci.org/content/jneuro/20/18/6820.full.pdf

Ictal Epileptiform Activity Is Facilitated by Hippocampal GABAA Receptor-Mediated Oscillations

How the extent and time course of presynaptic inhibition depend on the action potentials of the neuron controlling the terminals is unknown. We investigated this issue in the striatum using paired recordings from cholinergic interneurons and projection neurons. Glutamatergic EPSCs were evoked in projection neurons and cholinergic interneurons by stimulation of afferent fibers in the cortex and the striatum, respectively. A single spike in a cholinergic interneuron caused significant depression of the evoked glutamatergic EPSC in 34% of projection neurons located within 100 microm and 41% of cholinergic interneurons located within 200 microm. The time course of these effects was similar in the two cases, with EPSC inhibition peaking 20-30 ms after the spike and disappearing after 40-80 ms. Maximal depression of EPSC amplitude was up to 27% in projection neurons and to 19% in cholinergic interneurons. These effects were reversibly blocked by muscarinic receptor antagonists (atropine or methoctramine), which also significantly increased baseline EPSC (evoked without a preceding spike in the cholinergic interneuron), suggesting that some tonic cholinergic presynaptic inhibition was present. This was confirmed by the fact that lowering extracellular potassium, which silenced spontaneously active cholinergic interneurons, also increased baseline EPSC amplitude, and these effects were occluded by previous application of muscarinic receptor antagonists. Collectively, these results show that a single spike in a cholinergic interneuron exerts a fast and powerful inhibitory control over the glutamatergic input to striatal neurons.

https://www.jneurosci.org/content/jneuro/27/2/391.full.pdf

Cholinergic Interneurons Control the Excitatory Input to the Striatum

The striatum is the main recipient of dopaminergic innervation. Striatal projection neurons are controlled by cholinergic and GABAergic interneurons. The effects of dopamine on projection neurons and cholinergic interneurons have been described. Its action on GABAergic interneurons, however, is still unknown. We studied the effects of dopamine on fast-spiking (FS) GABAergic interneurons in vitro, with intracellular recordings. Bath application of dopamine elicited a depolarization accompanied by an increase in membrane input resistance (an effect that persisted in the presence of tetrodotoxin) and action-potential discharge. These effects were mimicked by the D1-like dopamine receptor agonist SKF38393 but not by the D2-like agonist quinpirole. Evoked corticostriatal glutamatergic synaptic currents were not affected by dopamine. Conversely, GABAergic currents evoked by intrastriatal stimulation were reversibly depressed by dopamine and D2-like, but not D1-like, agonists. Cocaine elicited effects similar to those of dopamine on membrane potential and synaptic currents. These results show that endogenous dopamine exerts a dual excitatory action on FS interneurons, by directly depolarizing them (through D1-like receptors) and by reducing their synaptic inhibition (through presynaptic D2-like receptors).

https://www.physiology.org/doi/pdf/10.1152/jn.00754.2001

Dopamine excites fast-spiking interneurons in the striatum.

1. The effects of blocking gamma-aminobutyric acid- and glycine-mediated synaptic transmission by bicuculline and strychnine on the neonatal rat isolated spinal cord were investigated by intracellu...

Spontaneous rhythmic bursts induced by pharmacological block of inhibition in lumbar motoneurons of the neonatal rat spinal cord

Spontaneous rhythmic bursting induced by coapplication of strychnine (1 microM) and bicuculline (20 microM) was observed with electrophysiological recording from pairs of lumbar ventral roots (usually L5) in an isolated preparation of the neonatal rat spinal cord. Bursting was insensitive to exogenously applied GABA or glycine, confirming that it was attributable to block of glycine and GABAA receptor-mediated inhibition. NMDA accelerated bursting in a dose-dependent manner. Complete coronal spinal transection at L3 or L6 level did not block bursting recorded from L5 or L2 roots, respectively. Gradual cutting of the cord along the midline through a sagittal plane preserved bursting activity in both disconnected sides but led to loss of synchronicity. Once the spinal cord was fully separated into left and right halves, regular bursting persisted on each side with no phase-coupling between the two preparations. Section along a frontal plane to remove dorsal horns and much of the central canal area did not affect burst frequency or left-to-right synchronicity, whereas it reduced burst duration. A quadrant preparation containing mainly a single ventral horn displayed enhanced burst frequency while bursts became very short events. Bath application of 5-hydroxytryptamine (30 microM) or NMDA (5 microM) increased burst frequency and decreased burst duration in all types of preparation except the isolated quadrants, in which brief bursts were accelerated but not shortened by these chemical agents. These results suggest that bursting induced by strychnine and bicuculline apparently relied on distinct mechanisms for burst triggering and intraburst structure. The first required a relatively smaller neuronal network that was confined to a ventral quadrant. Intraburst structure was dependent on a larger circuitry comprising either both ventral horns or one side of the spinal cord including more than two segments.

https://www.jneurosci.org/content/jneuro/16/21/7063.full.pdf

Enrico Bracci

Papers

Ictal Epileptiform Activity Is Facilitated by Hippocampal GABAA Receptor-Mediated Oscillations

Cholinergic Interneurons Control the Excitatory Input to the Striatum

Dopamine excites fast-spiking interneurons in the striatum.

Spontaneous rhythmic bursts induced by pharmacological block of inhibition in lumbar motoneurons of the neonatal rat spinal cord

Localization of Rhythmogenic Networks Responsible for Spontaneous Bursts Induced by Strychnine and Bicuculline in the Rat Isolated Spinal Cord