Abstract
Many kinds of brain injuries (e.g. stroke, amnesia, concussion, brain tumours, chronic alcoholism, encephalitis) or neurodegenerative diseases like Alzheimer’s disease or dementia commonly lead to memory deficits and/or cognitive impairments in the form of amnesia in several different degrees of severity. This is more common in individuals above the ages of 65. The number of individuals suffering from brain injury or neurodegenerative diseases is increasing in industrial societies like New Zealand due to increasing numbers of elderly people.
Two major regions appear to cause severe memory deficits when injured. These are the medial temporal lobe (including structures such as the hippocampus) and the diencephalon (including structures such as the thalamus). Damage to hippocampus has for example been shown to result in severe memory deficits. Likewise, damage to the diencephalon has been shown to disrupt memory processes. More specifically, damage to the anterior portion of the thalamus has been suggested as one of the main factors causing diencephalic amnesia. Another structure that has been implicated in memory processes is the prefrontal cortex, which is connected to structures both in the medial temporal lobe and in the diencephalon. The prefrontal cortex, the thalamus and the hippocampus are all connected within the Papez circuit.
A recent study conducted by Loukavenko, Ottley, Moran, Wolff, and Dalrymple-Alford (2007) suggested that environmental enrichment (EE) can ameliorate the behavioural effects of lesions to the anterior thalamic nuclei. EE has also been shown to ameliorate effects of other types of brain injuries, including damage to the hippocampus. However, it is still not clear at which level of the brain EE operates. Identifying the underlying mechanisms would be a major step forward in developing therapies for clinical diencephalic amnesia.
This thesis investigates the interaction of anterior thalamic lesions and EE treatment at several different levels within the brain: 1) intrinsic excitability of hippocampal CA1 pyramidal neurons via intracellular in vitro recording; 2) synaptic transmission and plasticity via extracellular in vitro recording in CA1; and 3) theta wave oscillations in the hippocampus (CA1 and dentate gyrus) and in anterior cingulate regions of the prefrontal cortex via gross extracellular recording in freely moving animals. Behaviour was assessed in several different tasks including foraging for chocolate hail, the Morris Water Maze test, and spatial working memory on a T-maze embedded in a plus-maze.
We found that all animals that received neurotoxin injections showed damage to the targeted thalamic areas as well as additional damage to adjacent regions and so all were included in our experiment. Lesioned animals showed the predicted memory impairment. EE did not have identical effects to those described by Loukavenko et al. (2007). They found improved overall performance (percent correct), while we found an improved learning rate, in animals from EE conditions.
Neither lesions to the ATN nor EE affected input-output measures, the size of the peak afterhyperpolarisation, or intrinsic synaptic transmission of CA1 pyramidal neurons. There was also no effect of lesions or EE on basal synaptic transmission, cell excitability or long-term potentiation. However, we found that lesions reduced pre-synaptic short-term plasticity at CA1 synapses and decreased recurrent inhibition; but these were unchanged by EE.
ATN lesions reduced theta power in the regions of the anterior cingulate cortex, area CA1, and the dentate gyrus. In the dentate gyrus, power was only reduced at lower frequencies. In the anterior cingulate, lesions decreased three distinct power bands (2 Hz, 5-8 Hz, and 10-13 Hz), while EE increased theta power in all three bands. This resulted in a similar pattern of theta power for lesioned animals from EE conditions compared to sham-injected animals from standard conditions. ATN lesions did not change CA1:prefrontal coherence. EE significantly increased CA1:prefrontal coherence. Dentate:prefrontal coherence was very low in all groups.
These data show that changes in cell excitability or synaptic transmission do not make a major contribution to the ‘recovery’ of memory loss via EE after damage to the anterior part of the thalamus; although ATN lesions affected short-term synaptic plasticity. EE influenced theta activity and so higher-order communication between the prefrontal cortex and the hippocampus. While the data do not speak to other types of change, or changes in other brain areas, they suggest that future studies should concentrate on higher order network properties such as theta activity rather than lower order properties such as excitability and long term potentiation in seeking a neural explanation for the memory recovery produced by EE.