Электрофизиологические корреляты нарушения обучения и памяти у старых животных тема диссертации и автореферата по ВАК РФ 03.00.13, кандидат биологических наук Оксман, Галина Яковлевна

• Оксман, Галина Яковлевна
• кандидат биологических наук
• 2005

Оглавление диссертации кандидат биологических наук Оксман, Галина Яковлевна

1. ВВЕДЕНИЕ

2. ОБЗОР ЛИТЕРАТУРЫ

2.1 Морфологическое строение гиппокампа

2.1.1 Основные системы гиппокампальных связей

2.1.2 Суммарная электрофизиологическая активность гиппокампа

2.1.3 Электрофизология переживающих срезов гиппокампа

2.2 Поведение и нейрональные процессы

2.2.1 Возрастные изменения в пространственной памяти на примере обучения в водном лабиринте Морриса

2.3 Феномен длительного увеличения синаптической пластичности (ДСП)

2.3.1 Механизмы возникновения и проявления ДСП

2.3.2 Поддержание ДСП

2.3.3. Изменения в ДСП при старении

2.3.4. Индукция ДСП при старении

2.3.5 Нарушение индукции ДСП совпадает с замедленным обучением у старых жи both ых

2.3.6. Поддержание ДСП при стрении

2.4 VDCC-зависимая форма ДСП

2.4.1 Индукция VDCC-ДСП

2.4.2 Изменения в VDCC ДСП при старении

2.5 Длительная синаптическая депрессия

2.6 Синаптические модификации при старении

2.7 Медленная следовая гиперполяризация

Введение диссертации (часть автореферата) на тему «Электрофизиологические корреляты нарушения обучения и памяти у старых животных»

В настоящее время около 15% населения мира составляют лица пожилого и старческого возраста. По прогнозам, к 2020 году их численность возрастет вдвое. В развитых странах лица пожилого возраста могут составить основную часть населения. Старение организма сопровождается целым рядом патологических растройств, таких как болезнь Альцгеймера, болезнь Паркинсона и деменция. В подавляющем большинстве случаев, даже при отсутствии выраженной патологии, отмечается снижение высших когнитивных функций, известное как умеренные когнитивные растройства (mild cognitive impairments, MCI). Предположительно, умеренные когнитивные растройства являются предшественниками более серьезной паталогии. В этой связи, изучение механизмов памяти, а также поиск и создание фармакологических препаратов, обладающих способностью замедлять/предотвращать развитие болезни и улучшать память в случае умеренных когнитивных расстройств, является одной из наиболее актуальных проблем нейробиологии и нейрофармакологии.

В процессе старения изменяется функционирование мозга, обусловленое как развитием дегенеративных процессов, так и интенсификацией компенсаторных явлений. При этом происходит ряд морфологических изменений в центральной нервной системе, которые в первую очередь приводят к ослаблению памяти и способности обучаться. Одна из основных проблем, стоящих перед учеными, это найти четкие критерии, разделяющие нормальное старение от патологии. Для решения этой задачи ученые широко используют лабораторных животных в качестве моделей как для нейрологических болезней, так и для нормального старения. Данные, полученые в результате экспериментов на лабораторных животных оказываются применимы для характеристики физиологических, генетических и молекулярных изменений, происходящих у людей во время старения. Так как в отличие от людей, лабораторные животные не развивают нейродегенеративные болезни, типа болезни Альцгеймера, то есть возможность изучения нормального старения в чистом виде. Однако одной из проблем, возникающих при работе со старыми животными является то, что фенотип нормального старения имеет большую вариабельность. Эта вариабельность часто наблюдается как между линиями животных, так и внутри одной линии, поскольку процесс старения опосредован целым рядом генетических факторов, проявляющихся в виде различных фенотипов. По этой причине при исследовании механизмов старения в последнее время стали использовать мышей с генетическими модификациями. Использование мышей с направленной мутацией генов, как модель для определенных генетических манифестаций в настоящее время широко применяется в исследованиях болезни Альцгеймера, синильных расстройств и болезни Паркинсона.

На данный момент большинство исследований в области памяти и старения сфокусировано на работе гиппокампа, его афферентных и эфферентных связях. Наряду с исследованиями в поведении, молекулярной биологии и биохимии существует широкий спектр изучения нейрональной пластичности мозга в процессе старения. Согласно современным представлениям, два основных клеточных механизма вовлечены в обучение и память. Первый, наиболее детально изученный, это длительная синаптическая потенциация (ДСП), представляющая собой продолжительное увеличение эффективности синаптической передачи в ответ на кратковременную высокочастотную стимуляцию (Bliss, 2003). Второй, менее изучений, это функциональные изменения возбудимости нейронов, регулируемые медленной следовой гиперполяризацией (МСГ) на уровне тела клетки (Daudal and Debanne, 2003; Disterhoft et al., 2004; Giese et al., 2001; Murphy et al., 2004; Sourdet et al., 2003). Оба механизма вовлечены в образование/усиление функциональных связей между нейронами либо за счет длительного увеличения силы синаптических связей, либо за счет продолжительного возрастания возбудимости нейронов. Известно, что нарушение любого из этих процессов отрицательно влияет на обучение и память лабораторных животных (Disterhoft et al., 2004; Giese et al., 1998). Таким образом, результаты данной работы могут быть полезны для более глубокого понимания механизмов лежащих в основе нарушений обучения и памяти при старении.

Цели и задачи исследования: Целью данного исследования было изучение элекрофизиологических показателей старения в методике in vitro, а также изучение взаимосвязи между обучением и электрофизиологическими показателями. Конкретные задачи данного исследования состояли в следующем:

1. Адаптировать методику переживающих срезов гиппокампа для работы со старыми животными.

2. Определить функциональные изменения МСГ под действием внутриклеточной стимуляции и фармакологических агентов.

3. Описать изменения МСГ у старых животных и проверить возможность фармакологической компенсации нарушений.

4. Сравнить УЭСС компонент ДСП у молодых и старых животных и проверить действие блокаторов кальциевых каналов на УБСС и ЫМЭА -зависимый компоненты ДСП.

5. Определить взаимосвязь между электрофизиологическими показателями и нарушением обучения у лабораторных животных.

6. Определить роль ДСП и МСГ в процессе обучения.

Научная новизна и практическая значимость. В настоящей работе впервые были описаны длительные функциональные изменения возбудимости нейронов. Было показано, что этот процесс, опосредованный через МСГ нарушен у старых животных. Была показана прямая зависимость между уровнем цАМФ в нейроне и амплитудой МСГ. Впервые была показана возможность компенсации нарушений у старых животных при использовании фармакологических агентов, которые повышают уровень цАМФ в нейроне. Это дает дополнительные сведения о биохимических процессах, которые вовлечены в механизм регуляции МСГ, а также возможность развития лекарственных препаратов для восстановления памяти в пожилом возрасте.

Данные, полученные при сравнении УЭСС компонента у молодых и старых животных подчеркивают роль кальция и кальциевых каналов при старении. Было показано, что блокаторы кальциевых каналов подавляют УОСС компонент ДСП, который увеличен у старых животных, что делает это направление перспективным для фармакологии старения.

Впервые было обнаружено, что снижение возбудимости нейронов, вследствии возрастания амплитуды МСГ является причиной нарушения пространственного обучения у мышей. Далее подробно была исследована роль в пространственном обучениии каждого из электрофизиологических процессов: МСГ и ДСП. Изучая корреляции электрофизиологических данных с каждым днем обучения животных в водном лабиринте Морриса, было впервые показано, что МСГ и ДСП являются двумя независимыми и последовательными компонентами механизма обучения. Это предлагает новый подход к изучению механизмов обучения и памяти, так как подобные корреляции еще не были описаны в научной литературе.

2. Обзор литературы

Заключение диссертации по теме «Физиология», Оксман, Галина Яковлевна

Выводы

1) У старых животных происходит увеличение амплитуды МСГ и снижение нейрональной возбудимости. Предположительно, снижение возбудимости нейронов приводит к нарушению или замедлению процессов обучения и памяти.

2) МСГ может опосредовать длительные функциональные изменения возбудимости нейронов. Активность фермента фосфодиестеразы 4, контролирующего уровень цАМФ в клетке, служит затворным механизмом этих изменений.

3) Процесс функциональной регуляции возбудимости нейронов нарушен у старых животных. Это нарушение возможно компенсировать при помощи фармакологической блокады фосфодиестеразы 4 ролипрамом.

4) При старении происходит возрастание VDCC компонента ДСП, который замещает NMDA зависимую ДСП. Эти нарушения богут быть компенсированы блокаторами VDCC каналов (нефедепин).

5) Амплитуда МСГ у молодых мышей линии DBA была выше, чем у C57BL6 мышей, что соответствовало их способности к обучению. Предполагается что молодые DBA мыши могут быть использованны как модель нарушения определенных аспектов обучения и памяти, связанных со старением.

6) Исходя из наших данных, МСГ, и ДСП представляют собой два независимых/последовательных нейрональных механизма памяти, причем увеличение нейрональной возбудимости (МСГ) является первичным по отношению к длительным изменениям синаптической связи (ДСП).

Так как старение может приводить к целому ряду функциональных нарушений, требуется развитие новых моделей для изучения нарушений обучения и памяти при старении.

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