Neuropeptide modulation of microcircuits

Abstract

Neuropeptides provide functional flexibility to microcircuits, their inputs and effectors by modulating presynaptic and postsynaptic properties and intrinsic currents. Recent studies have relied less on applied neuropeptide and more on their neural release. In rhythmically active microcircuits (central pattern generators, CPGs), recent studies show that neuropeptide modulation can enable particular activity patterns by organizing specific circuit motifs. Neuropeptides can also modify microcircuit output indirectly, by modulating circuit inputs. Recently elucidated consequences of neuropeptide modulation include changes in motor patterns and behavior, stabilization of rhythmic motor patterns and changes in CPG sensitivity to sensory input. One aspect of neuropeptide modulation that remains enigmatic is the presence of multiple peptide family members in the same nervous system and even the same neurons.

Figure 1

Schematic illustrations showing that peptidergic modulation occurs at multiple sites. (a) Neuropeptides modulate the cellular and synaptic properties of neurons at every processing stage of microcircuits, including their feedforward (e.g. exteroceptors and projection neurons) and feedback (e.g. muscle sensory neurons) inputs, their effectors (e.g. motor neurons and muscles) and the microcircuit itself. These modulatory actions collectively alter the behavioral output of these systems. Red-filled arrows indicate sites of peptide modulation. Red outlined arrows indicate neurons that use neuropeptide transmitters. (b) Neuropeptides act presynaptically to alter transmitter release, commonly via second messenger systems (represented by white arrows) that are activated by neuropeptide binding to GPCRs. These neuropeptides (red circles) can be delivered from external inputs to a presynaptic site (site 1) or as retrograde messengers from the postsynaptic neuron (site 2). In addition to modulation of synaptic properties, neuropeptides can act via GPCRs to alter intrinsic currents (site 3). (c) Left, Metabotropic receptor activation can selectively regulate neuropeptide (red circles) release from a presynaptic terminal [39^••]. Right, In addition, peptide binding to presynaptic GPCRs can regulate peptide release (and possibly small molecule transmitter release as well; white circles) [18^••].

Figure 2

Schematic illustrations representing peptidergic modulation of microcircuit output. (a) Peptidergic modulation of CPG neurons can select the set of active neurons and thereby establish a network state that determines the output elicited by a parallel input [57^••]. Left, For example, Input 1 activates specific CPG neurons (green circles) to drive a particular motor neuron firing pattern (green) and elicit Output 1. Right, In contrast, in the presence of a particular neuropeptide, the same Input 1 now elicits a distinct output (Output 2) by activating different CPG neurons (red circles) while inhibiting the formerly active CPG neurons (white circles). To further ensure selection of Output 2, the peptide activates feedforward loops by enhancing excitatory and inhibitory synaptic actions from an “upstream” CPG neuron onto its “downstream” CPG targets (not shown; see [57^••]). Symbols: Colored (red, green) circles, active neurons; grey circles, inactive neurons; white circles, inhibited by peptide input. (b) Peptidergic modulation can be module-specific [19^••]. The left motor neuron receives alternating excitation (Phase 1) and inhibition (Phase 2) from the CPG during a two-phase rhythmic motor pattern. The activity of this motor neuron is directly modulated by a peptidergic input (red). The right motor neuron receives concurrent excitation and inhibition from the CPG during both phases of the rhythm. This motor neuron is indirectly modulated by the peptidergic modulation of CPG neurons. Symbols: +, excitation; −, inhibition; colored (blue, green) circles, active neurons; grey circles, inactive neurons.

Figure 3

Schematic illustrations of the functional consequences of neuropeptide modulation. (a) Left, Middle: Peptidergic modulation (red) solely to the CPG increases the rhythm frequency, shortening the duration of CPG neuron activity during each cycle. This in turn causes fewer motor neuron action potentials per cycle and weaker muscle contractions. Right, The addition of peripheral modulation by the same peptide (released by a motor neuron) provides feedforward compensation. In this latter case, there is a faster motor neuron firing frequency and a strengthened muscle response to motor neuron input, maintaining behaviorally-appropriate muscle contractions despite the shorter duration of this phase of the motor pattern [20^••]. (b) Peptidergic modulation of a CPG feedback synapse is necessary for reducing the variability in the cycle duration during rhythmic motor activity [70^••,71]. Left, Middle: Peptidergic modulation (red) increases the frequency of rhythmic output relative to control. Right, When the peptide-enhanced feedback synapse is selectively suppressed (white synapse), the peptide modulated intrinsic properties of circuit neurons maintain the faster rhythm, but the cycle duration is more variable. Sine wave indicates endogenously oscillatory pacemaker neuron. (c) Peptidergic modulation gates out sensory feedback [39^••]. Left, A modulatory input uses peptide transmitter (red circle) binding to its receptor (blue) to activate an intrinsic current in a CPG neuron. This modulation helps generate a particular rhythmic motor pattern in the isolated nervous system. Middle, The inclusion of sensory feedback decreases the release of this peptide via presynaptic inhibition, slowing activation of the intrinsic current and thereby slowing the rhythm. Right, Modulation by a peptide hormone (green circle) gates out the influence of the sensory input, stabilizing the motor pattern and decreasing its sensitivity to perturbation. This is accomplished by the actions of the peptide hormone converging onto the same intrinsic current activated by the peptidergic input in the circuit neuron, albeit via a different receptor (Iight blue) [13^••,28^••].