Calvin K. Young, PhD

BSc(Hons) Biochemistry, University of Otago, New Zealand

BSc(Hons) Psychology, University of Otago, New Zealand

MSc Psychology, University of Otago, New Zealand

PhD Behavioural Neuroscience, University of Calgary, Canada

Optogenetic identification of hippocampal dentate granule cells (current work)

The hippocampal dentate gyrus is populated with many different cell types. Even among the pricinpal cell type (granule cells), many subtypes exist. This project explored methods to selectively target dentate granule cells for channelrhodopsin (ChR2) expression. Through light-triggered depolarization via ChR2, the technique can be used to identify genetically targeted cell populations electrophysiologically. 

Cortico-hippocampal theta oscillation coupling during spontaneous exploratory behaviour

       Inter-regional theta coherence has been linked to many aspects of learned behaviour, but their significance during spontaneous, naturalistic behaviour remains unclear. In this work, I show that medial prefrontal cortices (mPFC) show higher theta coherence with the hippocampus, cingulate and retrosplenial cortices during active exploration. I also demonstrate that theta oscillations can be independently expressed in the mPFC, hippocampus and retrosplenial cortex. A resting state 3-4 Hz oscillation in the mPFC was also observed in during quiet immobility.

What are oscillations good for and how to examine their interdependencies

            Brain oscillations are fluctuations of ion flow in and out of cells, reflecting mostly synaptic and slower currents involved maintaining resting membrane potential. Their role as an epiphenomenal secondary measure of local excitability, how they may coordinate local and distal brain activities and methods to reveal the nature of such coordination are summarized in this review.

Brain oscillations as a tool for activity coordination across the brain

            For decades hippocampal theta oscillations have been studied exclusively within the hippocampus. With increasing reports of behaviour-dependent theta coupling between distant brain areas, slower frequency brain oscillations have emerged as prime candidates to probe whole brain function. Recent advances of how coupled field and spike activities are gated and controlled, as well as future prospects of decoding brain oscillations are summarized.

Neuromodulation of striatal-hippocampal theta coupling

Striatal-hippocampal theta coupling has been reported to increase when an animal are required to choose. We find that haloperidol, a dopamine blocker, slowed hippocampal theta oscillations and disrupted striatal-hippocampal theta coupling while animals remained immobile. Posterior hypothalamic stimulation increased striatal-hippocampal theta coherence and facilitated locomotion. These data suggest dopamine is an important neuromodulator for striatal-hippocampal theta coupling, and that PH stimulation can restore such interactions in haloperidol treated animals through unknown mechanisms.

Determining the direction of information flow during learning

       The supramammillary nucleus in the hypothalamus has been identified as an independent theta oscillator and a key contributor for the expression of hippocampal theta oscillations. Reciprocal polysynaptic connections exist between the SuM and the hippocampus; thus the direction of theta modulation remains unclear. This study examined SuM-hippocampal theta interactions as a simplified direct, closed-loop circuitry during water maze learning. We demonstrated in real-data simulations that reciprocal theta modulation between the SuM and hippocampus is possible and may mediate learning.

Posterior hypothalamic nucleus as a novel deep brain stimulation site for parkinsonian akinesia

       A hallmark of Parkinson's disease is the inability or slowness to initiate and maintain movement. When drugs fail, deep brain stimulation (DBS) remains the only efficacious treatment for many. Traditional stimulation targets have limited therapeutic effects. Stimulation of the posterior hypothalamic nucleus (PH) induces vigorous locomotion in rats. We made animals parkinsonian with a high dose of haloperidol and rescued akinesia with PH-DBS in an active avoidance paradigm.

PH-DBS restores active avoidance in a rodent model of Parkinson's disease

            To follow up our previous findings (above), we used bilateral injections of the neurotoxin 6-hydroxydoamine to recreate dopaminergic cell depletion in the nigrostriatal pathway seen in Parkinson's disease. The animals were severely akinetic but PH-DBS rescued previously learned active avoidance task, cementing the relevance of PH-DBS in parkinsonian akinesia.

Negative effects of PH-DBS on motor function

       Although we have shown PH-DBS is a powerful facilitator of organized locomotion, it is not clear if this can be generalized outside of an active avoidance paradigm. I trained the animals to perform skilled forelimb use as well as simple bar-pressing for food pellets. PH-DBS, with or without haloperidol treatment disrupted the performance of these motor behaviours despite facilitating locomotion in general. Anatomical mapping show PH-DBS at the most rostro-dorsal aspect of the PH facilitated locomotion without producing other motor or behavioural abnormalities. These findings suggest PH-DBS may strengthen only the locomotion aspect of motor function in general, and its therapeutic effects are dependent on precise anatomical targeting.

Physiological correlates of PH-DBS reversal of akinesia

       The PH is reciprocally connected to different brain systems and can be seen as a diencephalic integrative centre with no clear membership to a particular modality. We used functional magnetic resonance imaging (fMRI) to identify possible downstream effectors of PH-DBS in anesthetized animals. Electrophysiological recordings confirmed that dorsal half of the neocortex became highly excitable during and after PH-DBS, which also reduced the electrical stimulation intensity needed to elicit bodily movements in anesthetized animals. Collectively, these data indicate an increase in cortical excitability may be key for the expression of increased naturalistic locomotion during PH-DBS in behaving animals.