Electrophysiology

We are interested in mechanisms of neuronal death during stroke and other neurodegenerative disorders. Currently, the focus is on a large ion channel called Pannexin-1, which has properties similar to some gap junction channels. The main goals of the research are to understand how pannexin-1 is activated during stroke, to determine what the consequenses of its activation are, and to investigate its normal physiological roles. To do this, we use state-of-the-art techniques including molecular biology, patch-clamp electrophysiology and in vivo multi-photon microscopy.

1. The physiology and function of somatosensory systems in the control of movement
2. Neuromotor rehabilitation in a motor syndrome induced by sensory loss.

The role of proprioceptive feedback in motor control and its CNS regulation by fusimotor efferent is studied:

• In acute electrophysiological experiments
• In mathematical modeling studies
• In morphometric investigations

A new animal model of chronic large-fibre deafferentation and peripheral sensory neuropathy is used to investigate the severe motor dysfunction that results from experimentally induced sensory loss and to explore the scope of neuromotor rehabilitation based on new methods of motor retraining.

The methods used include:

• Chronic and acute electrophysiology
• Kinematic and behavioural analysis of motor patterns
• Histology and morphometry of sensory neurons
• Labelling and morphometric analysis of functionally identified single neurones

My research comprises most aspects of audition with an emphasis on the electrophysiology of the auditory system in experimental animals, and is specifically focused on the role that is played by neural synchrony in the coding of complex (e.g., speech like) sounds in the auditory cortex. For that purpose extracellular single-unit recordings are made with electrode arrays (8 or 16 electrodes) simultaneously from 25-50 neurons from the auditory cortex of cats and kittens in response to a wide variety of complex stimuli. The data are analyzed with respect to both neural interaction, and single unit and population stimulus-response relationships. We developed an animal model of tinnitus to further our understanding of this disorder and, by comparison with the effects of external sounds of similar nature, to investigate how normal and pathological sound sensations are encoded in the central nervous system and the role of cortical reorganization played herein. I currently focus on the effects of long-term non-traumatic sound exposure on cortical activiry and organization. These effects occur at sound levels well below the safe standards for occupational noise exposure, which are based solely on hearing loss and not on hearing problems. We have shown that stimulating continuous or intermittently, to mimic occupational/recreational noise exposure interspersed with quiet periods (sleep), with particular sounds produces long-lasting decreases in the cortical representation of these sounds. This is expected to affect the perception of communication sounds, and may also lead to hypersensitivity for sounds with frequencies at the edge of the exposure spectrum, as well as to tinnitus (without the usual comorbid hearing loss). Extensive parametric studies into these effects are planned for the coming years.

The long-term objective of my research program is to contribute to the understanding of the hippocampal formation and its related structures (limbic cortex). My guiding hypothesis has been that these structures play a role in sensorimotor integration. Specifically, I have posited that certain components of the neural circuity in limbic cortex function in the capacity of providing voluntary motor system with continually updated feedback on their own performance relative to changing environmental (sensory) conditions. A crucial aspect of this performance is the intensity with which the motor programs are initiated and maintained. The components of the neural circuitry involved in sensorimotor integration are those underlying the production of oscillation and synchrony (theta) in limbic cortex. Therefore, the main approach of my research has been to use electrophysiological, neuropharmacological and behavioural techniques to elucidate the extrinsic and intrinsic properties underlying oscillation and synchrony  in limbic cortex. The properties of oscillation and synchrony are characteristic of many neurons throughout the central nervous system. Part of my research program over the years has been investigating the role of the posterior hypothalamus (PH) as part of the ascending brainstem hippocampal synchronizing system. My lab recently demonstrated that high frequency electrical stimulation (DBS) of the PH reverses akinesia in two seperate animal models of Parkinson's Disease and we are currently carrying out research into the mechanisms of this effect.

MolecularPhysiology of Membrane Calcium Transport and the Control of Cellular Homeostasis

Overall Research Interests
The broad subject of investigation in the Lytton laboratory is the control of calcium homeostasis and ubiquitous second messenger whose cytoplasmic concentration regulates a host of diverse biological events including muscle contraction, neurotransmitter secretion, hormone signaling, vesicle targeting and cell cycle control. We study proteins that transport calcium across membranes using molecular, biological, cellular and physiological techniques to understand structure, function and regulation.

Cardiac Na/Ca-Exchanger
One area of focus concerns the cardiac Na/Ca-exhanger. This plasma membrane transporter plays an essential role in controlling myocyte calcium concentrations during excitation-concentration; coupling activity of the exchanger is regulated by calcium binding to its larger cytoplasmic loop. The membrane coupled calcium binding to transport activation is currently under investigation. Various proteomic proteins applied to purified components, as well as electrophysiology on recombinant systems, will be used to answer these questions.

Neuronal Na/(Ca+K)-Exhangers
A second area of focus concerns a family of potassium-dependent Na/Ca-exchangers (NCKX) which are abundant in brain neurons. The unique roles these exchangers play in neuronal physiology is being studied using recombinant structure-function studies, cell biological analyses, and genetically engineered animals, work is currently focused on two of these transporters, NCKX2 and NCKX4. The former appears to play a role in hippocampal plasticity underlying motor learning and working memory consolidation. The other appears to play a pivotal role in the normal function of brain circiuts underlying feeding behaviour and satiety. Current efforts are directed towards understanding the mechanisms that lead from exchanger activity to the regulation of these important physiological processess.

Dr. Roth is an active researcher and teacher in both toxicology and pharmacology at the undergraduate, graduate and postgraduate levels. In addition to his teaching activities, he has been active in the development of curriculum. He has been involved in medical research for over three decades with interest in neuropharmacology, environmental toxicology, and medical pharmacology including cellular and mollecular mechanisms of anesthetic agents. His reseach in neurotoxicology focuses on the effects of various atmospheric pollutants such as hydrogen sulphide, sour gas, aerosols and volatile organic compounds on developing and mature nervous systems. He has collaborated his research with investigators in North America, Europe and Japan.

The goal of my lab is to understand how physiological and behavioural challenges lead to long-term changes in neural circuitry.  We focus on neurons that coordinate an organism's response to stress, with a particular interest in clarifying how the molecules released at the onset of a stressful stimulus leave a lasting imprint on how ‘stress-relevant' circuitry functions.  Within this context, we conduct experiments that will allow us to understand the fundamental rules that govern cell to cell communication within the hypothalamus and elucidate the molecular machinery that contributes to changes in synaptic function which, in turn, may be critical for changing network output. 

We are currently exploring three lines of investigation:

• We have demonstrated that glial cells can permanently increase the strength of excitatory, glutamatergic synapses in the paraventricular nucleus of the hypothalamus. We are now focused on elucidating the extent of this novel interaction between glial cells and neurons and will examine the role of this interaction during physiological challenges.
• Based on new observations that homeostatic set points in vivo are defended by metaplastic synaptic changes, we are now exploring additional mechanisms through which the activity-dependent release of retrograde signals impacts synaptic transmission.
• The inhibitory synapses onto neuroendocrine parvocellular neurons, the "command" neurons of the stress axis, exhibit remarkable state-dependent plasticity. We have shown that the onset of stress is accompanied by a loss of GABA inhibition due to a collapse of transmembrane chloride gradients. We are now pursuing the cellular and molecular mechanisms that underline this remarkable switch. Furthermore, we are exploring the impact of repetitive stress on synaptic function/plasticity in this system.

We use a number of experimental techiques to answer the above questions. These include, but are not limited to: patch clamp recordings from neurons in brain slices for the measurement of excitatory and inhibitory synaptic currents; UV laser uncaging of bioactive molecules; immunohistochemistry for the labeling of receptors and neuronal subpopulations.