The dorsolateral septal nucleus (DLSN) is an integral link in the septohippocampal pathway (DLSN - Medial septum-Diagonal Band of Broca - hippocampus - DLSN). Although earlier anatomical studies had demonstrated its essential position in this pathway, the functional roles of neurons within the DLSN were unclear. We have utilized an in vitro brain slice preparation from rats to record intracellularly from the DLSN in order to provide fundamental information about the physiological, pharmacological, and anatomical properties of individual DLSN neurons. Our work and lesion studies with ibotenic acid support our original hypothesis that the DLSN may serve as site for the induction, maintenance, and expression of theta rhythm. This study will test four hypotheses which suggest cellular mechanisms to explain the induction of theta rhythm in the DLSN.
Four specific aims will be addressed to test each of these hypotheses: 1) determine whether specific subtypes of cholinergic or GABAergic receptors can induce theta rhythm by regulation of voltage-dependent conductances on specific types of DLSN neurons; 2) determine if activation of cholinergic of GABAergic receptor subtypes can produce disinhibition in the DLSN and the induction of theta rhythm; 3) characterize the subtypes that modulate a non- specific cationic conductance which can induce theta rhythm; and 4) characterize the pharmacology of a metabotropic excitatory amino acid receptor which can induce LTP and possibly theta rhythm in the DLSN. We suggest that theta rhythm functions normally to facilitate (motivate) an individual to adapt (plasticity) and to facilitate and mediate such complex behaviors as learning and memory. If theta rhythm is not expressed or is expressed excessively, as under unusual emotional circumstances, e.g. stress; or in disease states, e.g., schizophrenia; or as a pathology of the aging process, e.g. dementia; or as a result of drug abuse; there may be an imbalance of three major transmitter systems, namely, GABAergic, cholinergic, and excitatory amino acid releasing. Each of these transmitter systems has been implicated in theta rhythm activity. As a result of this imbalance, aberrant behavior, rather than facilitation of normal behavior, occurs. This study will provide important basic information that may be applicable to clinical problems in mental health, since modification of theta rhythm and septal neuronal activity have been implicated in both normal and abnormal expressions of our emotions and in both normal and abnormal cognitive processes. Specific mental disorders that may benefit include: schizophrenia, anxiety, depression, dementia, Alzheimer's disease, and epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH039163-06
Application #
2244728
Study Section
Neurosciences Research Review Committee (BPN)
Project Start
1985-04-15
Project End
1996-08-31
Budget Start
1993-09-01
Budget End
1996-08-31
Support Year
6
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Texas Medical Br Galveston
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041367053
City
Galveston
State
TX
Country
United States
Zip Code
77555
Hasuo, H; Akasu, T; Gallagher, J P (1996) Muscarine activates a nonselective cation current through a M3 muscarinic receptor subtype in rat dorsolateral septal nucleus neurons. J Neurophysiol 76:2221-30
Zheng, F; Gallagher, J P; Connor, J A (1996) Activation of a metabotropic excitatory amino acid receptor potentiates spike-driven calcium increases in neurons of the dorsolateral septum. J Neurosci 16:6079-88
Phelan, K D; Sacaan, A; Gallagher, J P (1996) Retrograde labeling of rat dorsolateral septal nucleus neurons following intraseptal injections of WGA-HRP. Synapse 22:261-8
Zheng, F; Hasuo, H; Gallagher, J P (1995) 1S,3R-ACPD-preferring inward current in rat dorsolateral septal neurons is mediated by a novel excitatory amino acid receptor. Neuropharmacology 34:905-17
Zheng, F; Gallagher, J P (1995) Pharmacologically distinct, pertussis toxin-resistant inward currents evoked by metabotropic glutamate receptor (mGluR) agonists in dorsolateral septal nucleus (DLSN) neurons. J Neurosci 15:504-10
Zheng, F; Gallagher, J P (1995) (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid-induced burst firing is mediated by a native pertussis toxin-sensitive metabotropic receptor at rat dorsolateral septal nucleus neurons. Neuroscience 68:423-34
Gallagher, J P; Zheng, F; Hasuo, H et al. (1995) Activities of neurons within the rat dorsolateral septal nucleus (DLSN). Prog Neurobiol 45:373-95
Zheng, F; Lonart, G; Johnson, K M et al. (1994) (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) induces burst firing via an inositol-1,4,5-triphosphate-independent pathway at rat dorsolateral septal nucleus. Neuropharmacology 33:97-102
Phelan, K D; Twery, M J; Gallagher, J P (1993) Morphological and electrophysiological evidence for electrotonic coupling of rat dorsolateral septal nucleus neurons in vitro. Synapse 13:39-49
Zheng, F; Gallagher, J P (1992) Metabotropic glutamate receptor agonists potentiate a slow afterdepolarization in CNS neurons. Neuroreport 3:622-4

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