1 2 3 4 5 6 7 8 9

James P. O’Callaghan, Ph.D. – Head, Molecular Neurotoxicology Laboratory and CDC Distinguished Consultant

304-293-0602

1 Medical Center Drive
320 BMRC
PO Box 9303
Morgantown, WV 26505

Affiliations

Physiology, Pharmacology, & Neuroscience; Rockefeller Neuroscience Institute

Graduate Training

PhD in Neuroscience, Stanford University, Stanford, CA

Fellowship

Postdoctoral Fellow, University of California Irvine, CA

Research Interest

Our long-term goal is to advance our understanding of the function, structure and
development of the cerebral cortex or neocortex. In mammals, the neocortex is where
it all comes together: where incoming sensory information, relayed from the sensory
periphery via the thalamus, is processed, where decisions about appropriate motor
responses are made, and where such motor actions are planned and controlled. The
neocortex is most highly evolved in humans, in whom it is the site of our highest
cognitive functions such as face and object recognition, episodic memory, attention
and language, and (as far as we can tell) also of more elusive functions such as
creativity, rational thought, moral sense, and consciousness itself. To achieve
all this, the neocortex has specialized into multiple sensory, motor and associational
areas, each consisting of myriads of synaptic circuits, but all constructed out
of the same basic building blocks – excitatory and inhibitory neurons. Excitatory
and inhibitory neurons are not homogeneous populations – rather, each class consists
of multiple subtypes with unique genetic, biochemical, morphological and electrophysiological
properties. These subtypes are interconnected synaptically within and among themselves,
as well as with the thalamus, according to a very specific “wiring diagram”. Our
working assumption is that deciphering the wiring diagram is the key to understanding
neocortical function.

We employ a three-pronged strategy aimed at gaining some insight into this complexity:
we are attempting to chart the wiring diagram, to understand how it is put together
during development, and to uncover how these circuits give rise to higher cortical
functions. To decipher the circuitry, we are performing paired intracellular recordings
in brain slices of mouse somatosensory cortex; we record from pairs of cortical
neurons or from thalamus-cortex pairs, and characterize their different patterns
of synaptic connectivity. To follow the circuit during early development, we culture
thalamocortical brain slices taken from early postnatal or embryonic animals, and
image thalamocortical axonal growth using time-lapse confocal microscopy. Lastly,
to understand how this circuitry gives rise to higher cortical functions, we are
beginning to record neuronal activity in awake, behaving mice. Our plan is to train
mice to perform object recognition tasks, and then examine how inactivation of
specific neuronal subtypes affects this behavior. These three different but complementary
approaches are described in more details in the “Research Topics” section. In all
three approaches we are using genetically modified animals, in which specific neuronal
subtypes are induced to express fluorescent proteins or light-activated channels;
we can then use light to turn on or off specific neuronal subtypes with an exquisite
spatiotemporal control, a method called optogenetics.

Cover image

Research Topics

Research Topic #1: Precise Synchrony by Mutual Inhibition

Synchronous firing is commonly observed in the brain, but both its neurobiological
meaning and its underlying mechanisms remain debated. Most commonly, synchrony
is attributed either to electrical coupling by gap junctions or to shared excitatory
inputs. Theoretical studies suggest that inhibitory synapses can also promote synchrony;
however, this has not been confirmed experimentally. In the cerebral cortex, fast-spiking
(FS) inhibitory interneurons are connected to each other by chemical synapses,
electrical synapses or both; somatostatin-containing (SOM) inhibitory interneurons
are connected to each other electrically, but not chemically; and mixed SOM-FS
pairs are connected chemically but not electrically. We found that FS-FS and SOM-FS
pairs, connected by inhibitory synapses but not coupled electrically, often fired
within one millisecond of each other, whether during epochs of network activity
or when activated in isolation. The degree of synchrony correlated with the strength
of the inhibitory connection. Importantly, synchrony was resistant to ionotropic
glutamate receptors antagonists but was strongly reduced when GABAA receptors were
blocked. We conclude that submillisecond coordination of firing can arise by mutual
synaptic inhibition alone, with neither shared inputs nor electrical coupling.
(See Hu et al. 2011; Ma et al. 2012; Agmon 2012; Hu and Agmon 2015.)

Figure 2

Research Topic #2: Development of Thalamocortical Axons

The mammalian neocortex receives sensory information about the animal’s immediate
external and internal environment, assesses it on a moment-by-moment basis and
makes decisions about the motor actions which are most likely to promote survival
and reproduction. Auditory, visual and somatosensory information is relayed to
the neocortex through the thalamus, each modality relayed from a dedicated thalamic
nucleus to a dedicated cortical area. Correct pathfinding, target selection and
synapse formation by thalamocortical axons is therefore a prerequisite for normal
cortical function, and identifying the cellular and molecular determinants of these
processes is of utmost basic and clinical significance. Most studies to-date tackled
these questions by examining discrete developmental time points in fixed tissue.
However, static “snapshots” cannot reveal the dynamics of axonal growth, pathfinding,
branching, arborization and target selection, developmental processes which can
only be examined in live, developing axons. In a collaboration between the Agmon
and Tucker labs, we are developing a novel preparation in which growth and development
of thalamocortical axons is directly observable in live tissue. Moreover, electrical
activity in the presynaptic axons or their postsynaptic targets can be modulated
by light, and thereby the long-debated role of electrical activity in thalamocortical
development can be examined in detail.

F

Research Topic #3: Exploring the Neural Correlates of Object Percepts in the Mouse

The mammalian cerebral cortex has evolved to transform inputs from multiple sensory
channels into integratedinternal representations of different aspects of an animal’s
environment, especially those with high survival value, and to use these representations
to make decisions about immediate or future motor actions. In conscious humans,
these internal representations underlie object percepts such as “apple” or “grandma”.
We know that such representations exist, because we can conjure them up at will
as mental images, and because of agnosia symptoms displayed by people with localized
brain damage; however, we still do not know how object identity is encoded in the
cortex, and what neural algorithms are used to determine it. Understanding the
neural computations underlying object recognition may be one of the most important
– and arguably, most attainable – challenges facing systems and cognitive neuroscience
today. Recent advances in methodologies for recording, imaging and manipulating
neuronal activity in head-restrained, behaving mice performing behavioral tasks
now offer researchers the opportunity to address these issues experimentally; however
object recognition has not yet been studied using these methods. We recently received
pilot funding to establish themethodology for exploring the neural correlates of
object perception and recognition in the head -restrained mouse. Such methodology
will open up object recognition and decision making, as well as the underlying
learning and memory process, to experimental inquiry at the unprecedented level
of cellular resolution now available in the mouse


Lab Personnel

Qingyan Wang

Lab Director

qiwang@hsc.wvu.edu

Hang Hu

Research Scientist

hahu@hsc.wvu.edu

Rachel Hostetler

Graduate Student

rh0020@mix.wvu.edu


Recent Publications

[2016]

[2015]

[2013]

[2012]

[2011]

[2008]

  • Tan Z, Hu H, Huang ZJ,
    Agmon A.
    Robust but delayed thalamocortical activation of dendritic-targeting inhibitory
    interneurons.

    Proceedings of the National Academy of Science USA (2008) 105:2187-2192.
    PMID: 18245383

[2006]

  • Ma Y, Hu H, Berrebi AS, Mathers PH,
    Agmon A.
    Distinct subtypes of somatostatin-containingneocortical interneurons revealed
    in transgenic mice
    .
    Journal of Neuroscience (2006), 26(19):5069-5082. [PDF © The Society
    for Neuroscience. Used by permission.]

[2003]

  • Jin X, Hu H, Mathers PH,
    Agmon A.
    Brain-derived neurotrophic factor mediates activity-dependent dendritic growth
    in non-pyramidal neocortical interneurons developing in organotypic cultures
    .
    Journal of Neuroscience (2003), 23(13):5662-5673. [PDF © The Society
    for Neuroscience. Used by permission.]
  • Agmon A, Wells JE.
    The role of the hyperpolarization-activated cationic current I(h) in the timing
    of interictal bursts in the neonatal hippocampus
    .
    Journal of Neuroscience (2003), 23(9):3658-3668. [PDF © The Society
    for Neuroscience. Used by permission.

WVU Rockefeller Neuroscience Institute