ЖУРНАЛ ВЫСШЕЙ НЕРВНОЙ ДЕЯТЕЛЬНОСТИ, 2004, том 54, № 2, с. 192-201
IN THE MEMORY OF MY MENTOR DR. OLGA S. VINOGRADOVA
УДК 612.821.6
Theta Rhythmieity in the Medial Septum: Entraining by the GABAergie Neurons
© 2004 r. Elena S. Brazhnik
Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Puschino State University of New York, Health Science Center, Brooklyn, USA, e-mail: elena@theta.downstate.edu Поступила 28.03.2003 г. Принята 26.05.2003 г.
The medial septal/diagonal band complex (MS/DB) is believed to play an important role in the generation and maintenance of the hippocampal theta rhythm, which has been implicated in the mnemonic and information-processing capacity of the brain. Although the physiological and morphological diversity of the septal neurons indicates their different functions, it is not known which cell type within the population contributes most critically to the theta rhythm. Here we review the chemical identity of different cell groups within the MS/DB complex, the anatomical connectivity between them, the electrophysiological properties of immunochemically-defined cell types, and their contribution to theta rhythmicity in the medial septum and the hippocampal theta rhythm. In order to better understand the mechanisms involved in rhythmic burst firing of the MS/Db neurons, a number of relevant theoretical models related to the generation/synchronization in neural networks are discussed.
Key words: diagonal band of Broca, hippocampus, rhythmic bursting, network oscillations, synchronization.
ТЕТА-РИТМИЧНОСТЬ В ЭЭГ МЕДИАЛЬНОЙ СЕПТУМ: ДОМИНАНТНАЯ РОЛЬ ГАМКЕРГИЧЕСКИХ НЕЙРОНОВ
В ЕЕ ФОРМИРОВАНИИ
Е. С. Бражник
Институт теоретической и экспериментальной биофизики, Пущино, Россия; State University of New York, Health Science Center, Brooklyn, USA
Медиальный отдел септум (медиальное ядро и ядро диагонального пучка Брока) считается критической областью для генерации гиппокампального тета-ритма, участие которого в процессах обработки информации, обучения и памяти доказано. Наличие двух иммуногистохимически идентифицированных нейронных групп в медиальной септум (холинергической и ГАМКергической) может свидетельствовать об их неодинаковом влиянии на ритмическое залповое поведение нейронов внутри структуры. Вместе с тем тип нейронов, активность которых определяет генерацию тета-ритмики, неизвестен. В обзоре приведены сведения о морфологических и электрофизиологических свойствах основных групп сеп-тальных нейронов, взаимовлиянии разных типов клеток и оценен вклад каждого из них в генерацию ритмической залповой активности. Обсуждены некоторые теоретические модели, описывающие генерацию/ синхронизацию ритмической активности в нейронных сетях и способствующие пониманию механизмов эндогенной генерации ритмической залповой активности нейронами медиального отдела септум.
Ключевые слова: диагональный пучок Брока, гиппокамп, ритмические залпы, осцилляции в нейронных сетях, синхронизация
Synchronized activity in mammalian brain known as the hippocampal theta rhythm appears with prominent regularity when the animal engages in exploratory behavior, which includes movements, sniffing and orienting, and in rapid eye movement (REM) sleep. Theta rhythm is regarded as a "correlate" of involvement of the hippocampus and other limbic regions in cognitive functions such as the information processing, selective attention, learning and memory (review in [6, 79]). The medial area of the septum (medial nucleus and nucleus of the diagonal band
of Broca, the MS/DB complex) is a critical region for generation of the hippocampal theta rhythm [68]. The majority of its neurons fire in rhythmic bursts, and their appearance is tightly correlated with the emergence of the hip-pocampal theta rhythm. Inactivation/lesion of the MS/DB area completely eliminates theta rhythm and theta rhyth-micity in the hippocampus and other brain structures (reviewed in [79]). The notion that the burst rhythmicity of the MS/DB neurons is intrinsic to the septum or to the individual neurons is supported by data from many experi-
ments, both in vivo and in vitro. Under all of the following conditions a proportion of MS/DB neurons retained their rhythmic burst firing: a) after septal deafferentation [80], b) during pharmacological blockade of cholinergic transmission in vivo [17, 23, 72], c) in cultured slices in normal media [62, 80], d) after pharmacological blockade of cholinergic and GABAergic transmission in combination with verified blockade of synaptic influences [81], e) in intraocular and intracortical grafts [80] and f) in cultured neurons in vitro [74]. In this manuscript, the chemical diversity of medial septal neurons, their anatomical connectivity, the electrophysiological properties of distinct cell types, and neurotransmitters contributing to bursting oscillatory behavior of the septal neurons are reviewed in conjunction with theoretical models of the generation/synchronization in neural networks in order to elucidate possible mechanisms underlying theta rhythmicity within the MS/DB complex and the hippocampal theta rhythm.
Major cell groups within the medial septal region
Histological evidence. The septal complex includes a heterogeneous population of neurons containing different neurochemicals (acetylcholine, parvalbumin, calretinin and calbindin). Although on the basis of classical histolog-ical preparations the septum was considered to be a non-laminated structure, the immunocytochemically-defined cell groups in this area have characteristic topographic localizations, receiving and sending their axons to distinct brain regions [45]. A large cell group within the MS/DB region consists of y-aminobutiric acid (GABA)ergic neurons that have been identified by the presence of the GABA synthesizing enzyme, glutamic acid decarboxylase (GAD) [12, 35, 46, 65, 66]. The GABAergic cells have been shown to contain the calcium binding protein parvalbumin (GABAergic PV-containing cells) [28, 46]. The population of GABAergic PV-containing cells was defined to occupy the middle area of the septal complex. This cell group receives distinct projections from the hip-pocampal GABAergic calbindin-containing interneurons and sends axons forward to the hippocampal PV-contain-ing interneurons [29, 75]. Another large cell group within the MS/DB region has been identified by immunoreactiv-ity to the acetylcholine synthetizing enzyme choline acetyltransferase (ChAT-immunopositive cholinergic neurons) [12, 35, 90]. In addition, some ChAT-positive MS/DB neurons contain peptide galanin or NADPH-dia-phorase as co-transmitters [61, 67]. The population of cholinergic cells is distributed in a more lateral part of the MS/DB complex. This cell group innervates both the hip-pocampal pyramidal cells and interneurons. Thus, both the ChAT-immunopositive cholinergic and the GABAer-gic PV-containing MS/DB neurons project to the hippocampus [3, 5, 52] and, therefore, have been suggested to contribute to the hippocampal theta rhythm [17, 29, 73]. A third, well-defined group of cells immunopositive for calretinin (CR) and GAD has been shown to locate between lateral border the medial septum and the medial area of the intermediate lateral septal nucleus [45, 56]. The septal
GABAergic CR-containing neurons represent a distinct population of cells in the MS/DB, which is innervated by the hippocampal and entorhinal outputs (afferents), but does not send her projections back to the hippocampus. This population of cells projects to the non-GABAergic, CR-containing neurons in supramammill-ary area of the hypothalamus, which is known to project to the septal complex and hippocampus [9, 56]. The GABAergic CR-containing neurons may also function as interneurons relaying hippocampal feedback to the MS/DB projection neurons [45]. A fourth distinct cell type, the calbindin-containing (CB) GAD-immunoposi-tive neurons, is assembled in a vertically longitudinal area located between the medial septal laminar containing the CR-immunopositive neurons and the lateral septal area [42]. Unlike the majority of the lateral septal neurons, which exhibit a great number of dendritic and somatic spines, these CB cells do not have spines on their soma and proximal dendrites [42]. In addition to the hippocalm-pal afferents, the GABAergic CB-positive neurons receive basket-forming axon terminals from the GABAer-gic PV-containing neurons located in the angular portion of the vertical limb of the diagonal band of Broca. These GABA-GABA synaptic connections represent functional interaction between two different types of septal GABAergic neurons. The GABAergic CB-containing neurons do not send their projections to the hippocampus, but innervate the subcortical areas (reviewed in [42]).
Altogether, the combined ChAT-positive (cholinergic) and GAD-positive (GABAergic, containing parvalbumin, calretinin and calbindin) neurons do not represent the total number of MS/DB cells. The existence of ChAT- and GAD-negative cell type has been recently reported. These cells may correspond to the glutamate/aspartate population of MS/DB neurons with intraseptal and extraseptal projections, which has been revealed utilizing [3H]-aspar-tate retrograde transport autoradiography [44]. This indicates that the glutamatergic MS/DB neurons may also contribute to the generation/regulation of the theta rhythm.
The latest revision of the chemical phenotype of MS/DB neurons by using single-cell reverse transcription-polymerase chain reaction (scRT-PCR) to detect mRNAs for ChAT and GAD contributed to further classification of the MS/DB neurons. It confirmed the previously identified MS/DB cell groups: ChAT-positive cells (cholin-ergic), GAD-positive cells (GABAergic), and ChAT- and GAD-negative (putative glutamatergic neurons, as determined by the presence of one or both vesicular glutamate transporters). This method also clearly revealed a subpopulation of MS/DB neurons with co-expression of ChAT
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