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Thomas E. Finger Lab

Neurobiology of the Chemical Senses


Thomas E. Finger is a professor of Cullular and Structural Biology. Here received is doctorate from the Massachusetts Institute of Technology.

Contact: 303-724-3436

Overview: The general scope of my research focuses on two broad interests: 1) What is the nature and function of diverse peripheral chemoreceptors, i.e. taste buds, olfactory receptor cells and solitary chemoreceptor cells? And, 2) How is sensory information represented within the brain to enable production of directed motor output?

CHEMORECEPTORS: STRUCTURE & FUNCTION
We utilize three distinct chemoreceptor systems in detecting and responding to chemicals in our environment: taste, solitary chemoreceptor cells and olfaction, including the vomeronasal system. Each of these modalities is mediated by distinct chemosensory cells associated with distinct cranial nerves.

Taste Buds
Taste buds consist of axonless, neuroepithelial receptor cells embedded in gustatory epithelia, e.g. of the tongue and palate.   The elongate cells of taste buds fall into 3 distinct morphological classes termed Types I, II, or III, distinguished by the type of apical microvillous specialization, the shape of the nucleus and by the presence or absence of various intracellular organelles (reviewed in Finger & Simon 2000). Recent studies utilizing immunocytochemistry and in situ hybridization indicate functional specialization of these morphologically-defined cell types.   Further, we are trying to understand the lineage relationships within a taste bud (does one cell type mature into another, or are they distinct morphotypes originating from different progenitor cells?).
Text Box: ecctoATPase staining in fungiform (above) and vallate (below) papillae. The enzyme is specific for ATP as shown by lack of staining with ADP substrate.
Type I cells form lamellar processes which embrace the other two cell types reminiscent of glial processes elsewhere in the nervous system (Finger & Simon 2000; Yee et al. 2001).   Type I cells exhibit neither detectable expression of taste receptors nor excitable membrane characteristics typical of neurons. Thus, Type I taste cells resemble glia in a number of ways and may function in a supportive or insulating role within the taste bud.   Our ongoing studies ( Bartel et al; AchemS abstract 2005) demonstrate that these same cells express NTPDase2 ( ectoATPase).   This enzyme is highly abundant in taste buds and most likely is involved in inactivation of ATP which may serve as a modulator or transmitter in this system.
Type II cells  are spindle-shaped cells with a large, round, clear nucleus. Subsets of these cells express various families of 7-transmembrane (7-TM) taste receptors.   However, the majority of these cells, including the gustducin-expressing cells, lack voltage-gated Ca 2+ channels and, at least in rats, lack identifiable synapses with afferent nerve fibers.   So the manner in which Type II cells transmit information to the primary afferent fibers is unclear, but may be either by direct release of transmitter or via communication with Type III taste cells.
Type III taste cells express neuronal features including the: 1) cell adhesion molecule, NCAM (Nelson & Finger 1993), 2) synapse-associated protein, SNAP25, 3) neurotrophin, BDNF (Yee et al. 2003) and 4) voltage-gated Ca 2+ channels. Type III taste cells show electrical excitability and form prominent synapses with gustatory afferent fibers (Yee et al. 2001, 2003). The fact that Type III cells form classical synaptic contacts with nerve fibers is curious given that the known taste receptor proteins – for umami (T1R1/3), sweet (T1R2/3) and bitter (T2R) -- all are expressed in Type II cells.
Taste Bud Development: My laboratory also has examined the question of how and when taste buds arise during development.Our studies (Stone, et al. 1995) have shown that taste receptor cells, unlike other receptor cells, arise from local epithelium rather than from the neurogenic ectoderm that includes neural crest, neural tube and cranial placodes.
Further, our ongoing studies demonstrate that the lingual epithelium exhibits molecular differentiation of presumptive taste buds prior to arrival of sensory nerve fibers (see Figure at right). Therefore, taste buds arise from intrinsic epithelial patterning rather than from neural induction. Our research will continue to examine the expression of epithelial patterning genes and neurotrophins in developing taste buds.
The neurotrophin BDNF and its cognate receptor, trkB, are required for the normal development of the taste periphery.   Genetic elimination of either BDNF or trkB results in the absence of nearly all   taste buds.   In addition to this important role during development, BDNF continues to be expressed in adult taste buds (Yee et al., 2003).   Currently, we are examining the tongues from conditional knockout mice in which the neurotrophin, BDNF, was excised from lingual epithelium in adult mice.   Use of conditional knockouts allow us to separate the function of neurotrophins and other signaling molecules in adulthood from the functional role of these molecules during development.   Preliminary results indicate a subtle phenotype to the adult knockout of BDNF, i.e. Type III taste cells do not appear completely normal.   Ultrastructural studies and more thorough light microscopic studies are currently underway to better characterize this deficiency.

Solitary Chemoreceptor Cells
Recently, we discovered a population of epithelial chemoreceptor cells, called solitary chemoreceptor cells ( SCCs), within the nasal epithelium of mammals (Finger et al., 2003).    SCCs are morphologically similar to the individual cells in taste buds but unlike taste cells, form distinct synapses onto cutaneous nerve fibers of the trigeminal nerve (Finger et al., 2003).   Also unlike taste buds, SCCs are not clustered into groups, but are scattered as isolated cells.   SCCs are distributed throughout the nasal cavity, with the highest numbers anterior (Finger et al., 2003), and then extending down the airways through the larynx and trachea.
While many trigeminal stimuli can diffuse across the nasal epithelium and interact with free nerve endings, lipophobic stimuli must find another way to activate the trigeminal nerve.   The apical process of SCCs extends to the surface of the epithelium and contain T2R “bitter” taste receptors which presumably activate G-protein coupled intracellular signaling cascades.   One transduction system that SCCs use is similar to that of type II (bitter-sensitive) taste cells since both cell types utilize similar transduction cascades including T2R bitter taste receptors, PLC b2, and the G protein a- gustducin.   Many bitter tasting substances are noxious and activate protective avoidance or rejection responses.   The presence of bitter taste receptors and synapses with trigeminal nerve fibers suggests that SCCs are providing a detection system for noxious airborne substances which would not otherwise be able to reach nerve endings terminating below the level of the epithelial tight junctions (Finger et al., 2003).
Recently we completed a study showing that the nasal SCC cells exhibit turnover and replacement as do most other epithelial cells, including olfactory receptor neurons and taste buds.   In the future we plan to utilize Ca 2+ imaging to study the function of these receptor cells.  
Future studies will utilize functional imaging and electrophysiological techniques to catalog the types of stimuli that activate the solitary chemoreceptor cells.   Also we will attempt to identify the neurotransmitters and neurotrophins used by these cells to interact with the innervating nerve fibers.

Olfactory Receptor Cells & Odor Representation in the Forebrain
The olfactory system performs the complex task of discerning biologically meaningful signals among a sea of environmental chemicals. These signals include conspecific signals such as pheromones as well as less-specialized signals such as those involved with feeding and orientation. To meet the challenge of discriminating meaningful signals, vertebrates have evolved at least two types of olfactory receptor neurons (ciliated and microvillous; and in fish, a third type known as crypt cells). A preponderance of evidence suggests that ORNs express only one/few receptors and that ORNs with the same receptor(s) project to common glomeruli in the olfactory bulb, thus establishing a chemotopic map.
We use both catfish and goldfish as vertebrate model organisms in which to study how odors are encoded by the system.   These species are advantageous because the odor “world” of these animals is well-defined, and limited to a few classes of relevant odorants: amino acids and nucleotides as feeding-related cues, while bile salts and sex steroids serve as social signals. We have used anatomical tracing and immunocytochemical means, in consort with electrophysiological studies, to correlate the structural type of receptor cell with odor classes to which the cells respond.   In both catfish and goldfish, microvillous and ciliated cells are specialized to detect different odorant classes.   Bile salts (social signals) are detected by ciliated ORNs utilizing Buck & Axel-type odorant receptors ( ORs) and the canonical g/ olf signaling cascade.   In contrast, nucleotides (feeding cues) are detected by microvillous ORNs which rely on vomeronasal type receptor molecules (V2R-like receptors) and other G-protein transduction cascades (Hansen et al., 2004).   Interestingly, amino acids (feeding cues) are detected by different   ciliated and microvillous ORNs. 
Despite the complexity of peripheral coding mechanisms for different odoratnts, the ORNs connect to the olfactory bulb so as to form an odotopic map, i.e a spatial map of different odorants. 
Ongoing studies in collaboration with J. Caprio (Louisiana State Univ.), investigate whether this odotopy continues in the higher-order olfactory targets of the forebrain.   Combined anatomical and electrophysiological studies demonstrate that although a type of odotopy persists into the forebrain, the forebrain odotopy is more related to odor context (social vs feeding) than to specific chemical structure of the odorant.

II. CENTRAL TRANSMISSION AND PROCESSING OF TASTE INFORMATION
Feeding behavior is regulated largely by gustatory cues in many vertebrates. In order for a potential foodstuff to be swallowed, it must trigger an appetitive gustatory cue. Anatomical, electrophysiological and pharmacological methods are being employed to study the neural organization of gustatory systems in goldfish and catfish, two highly gustatory species. Goldfish have evolved an elaborate specialization of the pharynx that is involved in sorting food from substrate (Lamb and Finger 1995). The neuronal machinery involved in this behavior is situated in an easily accessible, laminated structure of the hindbrain. This organization is conducive to in vitro slice physiology and pharmacology as well as to in vivo electrophysiological study.
Text Box: Schematic diagram showing hypothetical synaptic arrangements being investigated. The primary afferent terminal utilizes glutamate acting on ionotropic postsynaptic receptors (iGluR) to depolarize the dendrite of the second-order cells. We have evidence for regulation of transmission at this synapse both by glutamate (acting through mGluRs), and by GABA (acting through GABAA and GABAB receptors). We also examine the possible role of presynaptic kainate receptors (KA-R) and the effects of neuropeptides on this system.
The elegant anatomical organization of this system in goldfish has facilitated studies of the circuitry and neurotransmitters of the brainstem gustatory complex. We have established that the neurotransmitter for primary gustatory fibers synapsing in the brainstem is glutamate acting through AMPA/ kainate and NMDA receptors on second-order neurons ( Smeraski et al. 1998 ;1999).   Furthermore, new data indicate that GABA plays an important role in modulation of the primary afferent input (Sharp and Finger 2002), although the identity and location (pre- or postsynaptic) of the relevant GABA receptors are unclear.   Our recent preliminary results also implicate presynaptic glutamate receptors in modulation of transmission across the primary afferent terminals. Our current experiments seek to resolve how primary gustatory afferent information is modulated at early stages of processing within the primary gustatory nucleus. In particular, we are using morphological and in vitro physiological approaches to assess whether presynaptic glutamate receptors and/or presynaptic GABA receptors may serve to modulate incoming gustatory activity (See Figure at Right).
We have developed an in vitro slice preparation of the brainstem gustatory nucleus in goldfish (the vagal lobe) equivalent to the nuc. of the solitary tract in mammals.   The laminated organization of this structure permits application of an in vitro slice preparation (Finger and Dunwiddie , 1992) shown schematically in the figure at right similar to the slice preparation used to study evoked field potentials in the hippocampus of mammals.   The recorded field EPSP reflects the summed activity of the aligned postsynaptic dendritic elements.
Text Box:
Evidence for modulation of afferent transmission in this system comes from slice recordings in which either glutamate or GABA agonists are applied, resulting in alteration of the evoked EPSP.   For example application of a mGluR agonist ACPD essentially eliminates the evoked EPSP.   We hypothesize that presynaptic mGluR receptors inhibit vesicle release from the primary afferent terminal.   Similarly, GABA agonists inhibit the EPSP, but it is difficult to dissociate pre- from post-synaptic effects in this preparation relying entirely on the evoked EPSP.   Accordingly, we will utilize Ca 2+ imaging to directly measure Ca 2+ influx into the primary afferent terminals.   In order to accomplish this, we fill the primary afferents in vivo with Ca-green dextran.   A vagal lobe slice then is prepared after an appropriate survival time (3-4 days) allowing for transport of the Ca-indicator to the central terminals.   Thus the only elements of the slice filled with the Ca-indicator are the primary afferents, hence any signal must originate from these processes.   We then image the slice preparation and can measure whether the various GABA or glutamate agonists alter the Ca-dynamics of the afferent terminals.   We predict that application of mGlu and GABA agonists will inhibit Ca 2+ influx which would result in decreased transmitter release.   We also are looking for molecular and morphological correlates (in situ hybridization, immunocytochemistry, or PCR) of the presence of GABA and glutamate receptors on the primary afferents, e.g. the expression of GABA- or glutamate receptor subunits in the ganglion cells of the primary afferents.

 
Selected Publications

Finger TE, Bottger B, Hansen A, Anderson KT, Alimohammadi H, Silver WL. (2003) Solitary chemoreceptor cells in the nasal cavity serve as sentinels of respiration. Proc Natl Acad Sci U S A. 100(15):8981-6.

Hansen A, Rolen SH, Anderson K, Morita Y, Caprio J, Finger TE. (2003) Correlation between olfactory receptor cell type and function in the channel catfish. J Neurosci. 23(28):9328-39.

Finger TE, Danilova V, Barrows J, Bartel DL, Vigers AJ, Stone L, Hellekant G, Kinnamon SC. (2005) ATP signaling is crucial for communication from taste buds to gustatory nerves. Science 310:1495-9.

Finger TE (2007) Sorting Food from Stones: The Vagal Taste System in Goldfish,  Carassius auratus. J . Comp. Physiol. A. 194(2):135-143. 

Kataoka S, Yang R, Ishimaru Y, Matsunami H, Sevigny J, Kinnamon JC, Finger TE. 2008. The candidate sour taste receptor, PKD2L1, is expressed by type III taste cells in the mouse. Chem Senses 33(3):243-254. 

Tizzano M, Dvoryanchikov G, Barrows JK, Kim S, Chaudhari N, Finger TE. 2008. Expression of Galpha14 in sweet-transducing taste cells of the posterior tongue. BMC Neurosci. 2008 Nov 13;9:110.

Finger, T.E. (2009) Evolution of Gustatory Reflex Systems in the Brainstems of Fishes. Integr Zool  4: 53-63. 

Hallock RM, Tatangelo M, Barrows J, & Finger TE (2009) Residual chemosensory capabilities in double P2X2/P2X3 purinergic receptor null mice: intraoral or postingestive detection? Chem Senses 34(9):799-808. 

Tizzano M, Gulbransen BD, Vandenbeuch A, Clapp TR, Herman JP, Sibhatu HM, Churchill ME, Silver WL, Kinnamon SC, Finger TE. (2010) Nasal chemosensory cells use bitter taste signaling to detect irritants and bacterial signals. Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3210-5. Epub 2010 Jan 26.