Grant: Discovery Grants Program - Individual

Over a life-time, one's brain is exposed to many challenges and insults, some of which can be neurologically devastating. For example, head injuries or high fever can create conditions that result in the development of epilepsy characterized by chronic recurrent seizures. Yet we know that mild and limited seizures in fetal brains is common during development and appears to be quite harmless; in fact, such mild seizures might  facilitate normal brain development. However, if the seizures are unrelenting, they can create conditions leading to neuropathology and/or epilepsy. Unrelenting seizures in the form of status epilepticus are normally very neurodestructive in adults. Yet we have discovered that previous development of 'kindled' seizures, through application of low intensity brain stimulation, can protect the adult brain from the neural devastation that normally  follows status epilepticus.  In our proposed experiments, we will examine different neural networks in the forebrain of rats that can be saved from severe insult through the kindling of different brain structures, as each structure is part of a different neural network. In each of these different networks, we will examine the types of brain cells that are either saved or lost, using standard histological methods. Then we will ask what kind of stimulation induces the neuroprotection, how long does it last, and if the same cell types are preserved in different structures at different times after kindling and/or our adjunct treatment of low frequency (1 Hz) brain stimulation applied to the kindled site. Further we will test whether the apparent histological normalcy of the networks is also reflected in their triggered seizure behavior (by the kindling stimulus) compared to before the insult, as well as in a variety of behavioral paradigms known to be associated with those networks and structures, including the open field, elevated plus maze, inhibitory avoidance and Morris water maze. Ultimately, we hope that a fuller understanding of this dramatic neuroprotection effect will lead to numerous prophylactic treatments (and more efficacious remedial treatments) to cope with the inevitable onslaught of serious life-time challenges that can compromise a neurologically sound and healthy future.