Tonic Nanomolar Dopamine Enables an Activity-Dependent Phase Recovery Mechanism That Persistently Alters the Maximal Conductance of the Hyperpolarization-Activated Current in a Rhythmically Active Neuron

Abstract

The phases at which network neurons fire in rhythmic motor outputs are critically important for the proper generation of motor behaviors. The pyloric network in the crustacean stomatogastric ganglion generates a rhythmic motor output wherein neuronal phase relationships are remarkably invariant across individuals and throughout lifetimes. The mechanisms for maintaining these robust phase relationships over the long-term are not well described. Here we show that tonic nanomolar dopamine (DA) acts at type 1 DA receptors (D1Rs) to enable an activity-dependent mechanism that can contribute to phase maintenance in the lateral pyloric (LP) neuron. The LP displays continuous rhythmic bursting. The activity-dependent mechanism was triggered by a prolonged decrease in LP burst duration, and it generated a persistent increase in the maximal conductance (G max ) of the LP hyperpolarization-activated current (I h ), but only in the presence of steady-state DA. Interestingly, micromolar DA produces an LP phase advance accompanied by a decrease in LP burst duration that abolishes normal LP network function. During a 1 h application of micromolar DA, LP phase recovered over tens of minutes because, the activity-dependent mechanism enabled by steady-state DA was triggered by the micromolar DA-induced decrease in LP burst duration. Presumably, this mechanism restored normal LP network function. These data suggest steady-state DA may enable homeostatic mechanisms that maintain motor network output during protracted neuromodulation. This DA-enabled, activitydependent mechanism to preserve phase may be broadly relevant, as diminished dopaminergic tone has recently been shown to reduce I h in rhythmically active neurons in the mammalian brain.

Frank Beach Award Winner: Steroids as neuromodulators of brain circuits and behavior

“…It appears that, once again, invertebrate models have begun to shed light on this complex issue. The concentration of dopamine in the hemolymph of spiny lobsters is at a low basal tone that changes slowly over time, whereas the concentration thought to be released within the STG is considerably higher and more transient (Rodgers et al, 2011). It remains to be determined whether the differential concentration of circulating steroids vs. neurosteroids can produce a similar basal tonic vs. elevated phasic modulation of neural circuits relevant to behavior (see Cornil, 2009; Cornil et al, 2012a for further discussion).…”

Robust circuit rhythms in small circuits arise from variable circuit components and mechanisms

“…In a set of intriguing studies, the Baro lab [47*, 48*, 61, 62] has studied the effects of high and low concentrations of dopamine, mediated by different receptors and signal transduction pathways on channel expression and motor pattern generation in the STG. These studies highlight the importance of distinguishing between the modulatory tone that can arise from steady but low concentrations of a neuromodulator and the changes that can occur with short-term activation by higher concentrations [47*, 48*, 61, 62].…”

Homeostatic plasticity of excitability in crustacean central pattern generator networks

“…However, dopamine also acts at high-affinity D1R receptors at far lower concentrations (~5 nM) to mediate a response that can regulate I H in an activity-dependent manner, precisely compensating for decreased I A via a concomitant calcineurin-dependent decrease in I H which restores LP phasing [32–34]. These findings demonstrate a mechanism by which modulation can provide flexibility and stability through a self-stabilizing feedback loop to maintain the I A :I H ratio, and that low levels of constitutive modulation can potentiate activity-dependent regulation of conductances [35]. Interestingly, these high-affinity D1 receptors also act on longer timescales to increase both of these ionic conductances through pathways that depend on transcription, translation, and RNA interference [36,37].…”

“…While neuromodulation can influence longer-term expression of channels in STG neurons (see above; [35–37,40]), only recently has there been evidence of direct activity-dependent feedback to the level of channel mRNAs. Temporal et al [46] recently performed such a study that decoupled the effects of loss of activity and neuromodulation as a result of decentralization of STG neurons (Figure 3D).…”