Christopher D. Howard

Methamphetamine neurotoxicity decreases phasic, but not tonic, dopaminergic signaling in the rat striatum

J. Neurochem. (2011) 118, 668–676.

A wireless IC for time-share chemical and electrical neural recording

Neurons communicate both electrically and chemically [1]. Extensive effort has been directed at monitoring these signals in awake animals to investigate the neural basis of behavior. While various measurement strategies have been employed in the past, electrophysiology (EPHYS) for single-unit recording [2] and voltammetry for neurotransmitter sensing [3] are established as the two best methods for probing neurotransmission at microscopic scales in real time.

High doses of amphetamine augment, rather than disrupt, exocytotic dopamine release in the dorsal and ventral striatum of the anesthetized rat.

J. Neurochem. (2011) 10.1111/j.1471‐4159.2011.07407.x

Methamphetamine-induced neurotoxicity disrupts naturally occurring phasic dopamine signaling

Methamphetamine (METH) is a highly addictive drug that is also neurotoxic to central dopamine (DA) systems. Although striatal DA depletions induced by METH are associated with behavioral and cognitive impairments, the link between these phenomena remains poorly understood. Previous work in both METH‐pretreated animals and the 6‐hydroxydopamine model of Parkinsons disease suggests that a disruption of phasic DA signaling, which is important for learning and goal‐directed behavior, may be such a link. However, previous studies used electrical stimulation to elicit phasic‐like DA responses and were also performed under anesthesia, which alters DA neuron activity and presynaptic function. Here we investigated the consequences of METH‐induced DA terminal loss on both electrically evoked phasic‐like DA signals and so‐called ‘spontaneous’ phasic DA transients measured by voltammetry in awake rats. Not ostensibly attributable to discrete stimuli, these subsecond DA changes may play a role in enhancing reward–cue associations. METH pretreatment reduced tissue DA content in the dorsomedial striatum and nucleus accumbens by ~55%. Analysis of phasic‐like DA responses elicited by reinforcing stimulation revealed that METH pretreatment decreased their amplitude and underlying mechanisms for release and uptake to a similar degree as DA content in both striatal subregions. Most importantly, characteristics of DA transients were altered by METH‐induced DA terminal loss, with amplitude and frequency decreased and duration increased. These results demonstrate for the first time that denervation of DA neurons alters naturally occurring DA transients and are consistent with diminished phasic DA signaling as a plausible mechanism linking METH‐induced striatal DA depletions and cognitive deficits.

A Neurochemical Pattern Generator SoC With Switched-Electrode Management for Single-Chip Electrical Stimulation and 9.3 µW, 78 pA rms , 400 V/s FSCV Sensing

This paper describes a system-on-chip (SoC) fabricated in AMS 0.35 μm 2P/4M CMOS for high-fidelity neurochemical pattern generation in vivo. The SoC uniquely integrates electrical stimulation with embedded timing management for generation of neurochemical patterns and 400 V/s fast-scan cyclic voltammetry (FSCV) sensing for subsequent assessment of fidelity in the generated profiles, and manages a novel switched-electrode scheme that eliminates the possibility of large stimulus artifacts adversely affecting electrochemistry. The SoC also leverages the discontinuous sampling inherent in FSCV to reduce the sensing power consumption by 87.5% to 9.3 μW from 2.5 V using a duty-cycled, 3rd-order, continuous-time, ΔΣ modulator (CT-ΔΣM) with an input-referred noise current of 78 pArms (dc - 5 kHz) within an input current range of ±950 nA. Utilizing a transfer function that relates electrical stimulation of dopamine axons traversing the medial forebrain bundle (MFB) to evoked extracellular dopamine dynamics in the dorsal striatum of the forebrain, the correlation coefficient between predicted and measured dopamine temporal profiles was found to be 0.95 in an anesthetized rat.

Phasic‐like stimulation of the medial forebrain bundle augments striatal gene expression despite methamphetamine‐induced partial dopamine denervation

Methamphetamine‐induced partial dopamine depletions are associated with impaired basal ganglia function, including decreased preprotachykinin mRNA expression and impaired transcriptional activation of activity‐regulated, cytoskeleton‐associated (Arc) gene in striatum. Recent work implicates deficits in phasic dopamine signaling as a potential mechanism linking methamphetamine‐induced dopamine loss to impaired basal ganglia function. This study thus sought to establish a causal link between phasic dopamine transmission and altered basal ganglia function by determining whether the deficits in striatal neuron gene expression could be restored by increasing phasic dopamine release. Three weeks after pretreatment with saline or a neurotoxic regimen of methamphetamine, rats underwent phasic‐ or tonic‐like stimulation of ascending dopamine neurons. Striatal gene expression was examined using in situ hybridization histochemistry. Phasic‐like, but not tonic‐like, stimulation induced immediate‐early genes Arc and zif268 in both groups, despite the partial striatal dopamine denervation in methamphetamine‐pretreated rats, with the Arc expression occurring in presumed striatonigral efferent neurons. Phasic‐like stimulation also restored preprotachykinin mRNA expression. These results suggest that disruption of phasic dopamine signaling likely underlies methamphetamine‐induced impairments in basal ganglia function, and that restoring phasic dopamine signaling may be a viable approach to manage long‐term consequences of methamphetamine‐induced dopamine loss on basal ganglia functions.

A miniaturized device for wireless FSCV monitoring of dopamine in an ambulatory subject

This paper reports on a miniaturized device for wireless monitoring of extracellular dopamine levels in the brain of an ambulatory rat using fast-scan cyclic voltammetry at a carbon-fiber microelectrode. The device comprises integrated circuitry for neurochemical recording fabricated in 0.5-µm double-poly triple-metal CMOS technology, which is assembled and packaged on a miniature rigid-flex substrate together with a few external components for supply generation, biasing, and chip programming. The device operates from a single 3-V battery, weighs 2.3 g (including the battery), and upon implantation successfully captures the effects of the psychostimulant amphetamine on electrically and non-electrically evoked dopamine neurotransmission in the caudateputamen region of an ambulatory rats forebrain.

Methamphetamine-induced neurotoxicity disrupts pharmacologically evoked dopamine transients in the dorsomedial and dorsolateral striatum

Phasic dopamine (DA) signaling, during which burst firing by DA neurons generates short-lived elevations in extracellular DA in terminal fields called DA transients, is implicated in reinforcement learning. Disrupted phasic DA signaling is proposed to link DA depletions and cognitive-behavioral impairment in methamphetamine (METH)-induced neurotoxicity. Here, we further investigated this disruption by assessing effects of METH pretreatment on DA transients elicited by a drug cocktail of raclopride, a D2 DA receptor antagonist, and nomifensine, an inhibitor of the dopamine transporter (DAT). One advantage of this approach is that pharmacological activation provides a large, high-quality data set of transients elicited by endogenous burst firing of DA neurons for analysis of regional differences and neurotoxicity. These pharmacologically evoked DA transients were measured in the dorsomedial (DM) and dorsolateral (DL) striatum of urethane-anesthetized rats by fast-scan cyclic voltammetry. Electrically evoked DA levels were also recorded to quantify DA release and uptake, and DAT binding was determined by means of autoradiography to index DA denervation. Pharmacologically evoked DA transients in intact animals exhibited a greater amplitude and frequency and shorter duration in the DM compared to the DL striatum, despite similar pre- and post-drug assessments of DA release and uptake in both sub-regions as determined from the electrically evoked DA signals. METH pretreatment reduced transient activity. The most prominent effect of METH pretreatment on transients across striatal sub-region was decreased amplitude, which mirrored decreased DAT binding and was accompanied by decreased DA release. Overall, these results identify marked intrastriatal differences in the activity of DA transients that appear independent of presynaptic mechanisms for DA release and uptake and further support disrupted phasic DA signaling mediated by decreased DA release in rats with METH-induced neurotoxicity.

Dopaminergic Signaling in Cost-Benefit Analyses: A Matter of Time, Effort, or Uncertainty?

Adaptive choice relies on valuation of commodities and behaviors in terms of their rewarding properties and cost of acquisition. The ability to monitor electrical and chemical signals within the brain while animals behave and respond to their environment offers a unique opportunity for understanding