Memory and Neurological Disorder Modeling

Human diseases can be investigated at the molecular level by developing animal models that show the symptoms and underlying brain pathologies of these diseases.

Human Alzheimer’s disease genes, for example, can be inserted into a mouse genome to produce very similar symptomatic and neurodegenerative changes as observed in human patients.  A number of such animal models have been developed that have different mutations that cause Alzheimer’s disease in different families across the world.  Together these families can account for about 6 % of the total number of Alzheimer’s disease cases.  The other 94% of Alzheimer’s cases do not have highly expressed genetic factors.  Instead, they are largely determined by risk factors such as age, preceding head trauma and defective cholesterol metabolizing enzymes.

Nevertheless, the genetic Alzheimer’s disease (AD) models most of the characteristic deficits as all forms of AD and, for this reason are extremely valuable for investigating the underlying causes of AD, diagnostics, and therapeutic drugs.  BRNI scientists have used three different AD models involving a single mutation, a double mutation and a five-mutation mouse strain.  With these models, BRNI research confirmed the sequence of events that occurs in the typical AD disease progression, elevation of soluble A Beta, loss of the synaptogenic enzyme, PKC epsilon, loss of brain synapses, impaired learning and memory and then, deposition of amyloid plaques.

Using such animal models, BRNI scientists have developed a class of AD therapeutics (See Drug Targets and Clinical Trials) to treat all of the characteristic symptoms as well as the underlying neurodegeneration that includes the loss of synapses, elevation of soluble A Beta and amyloid plaques.  These drugs, in turn, greatly enhance the survival of these AD model mice.  Such models have also increased our understanding of critical molecular deficits, such as the PKC isozymes alpha and epsilon, providing valuable assays for the early diagnosis of AD in humans (See Diagnostics).

Stroke Models

BRNI scientists have also applied three different models of stroke to investigate the underlying neurodegenerative changes and the development of effective treatments to prevent these changes.  One model involves preventing blood flow through the internal carotid arteries to the brain – exactly as often occurs in patients before a stroke.  Another model involves obstructing flow in other vessels as well, and a third model, pursued in collaboration with the WVU Department of Neurosurgery, involves obstructing blood flow to areas of the brain critical for the control of body movements.

With all three animal models of stroke, BRNI scientists identified characteristic symptoms as well as loss of neurons and synapses.  We then tested and validated our PKC Activator platform to be very effective in preventing both the symptoms and pathologic deficits in these stroke models.

Models of Traumatic Brain Injury

BRNI scientists have optimized and applied a model of mild traumatic brain injury using a quantifiable weight drop.  This model involves subsequent impairment of learning and memory as well as the loss of synaptic connections.  BRNI therapeutics again proved effective at preventing these symptomatic and pathologic changes in the brain.  Other models of TBI are also being pursued in collaboration with scientists and physicians at centers of research sponsored by the Department of Defense.

Models of Depression

A psychiatric disease that is amenable to animal model development is depression.  Based on the conceptual framework of learned helplessness, research in many laboratories have constructed experimental circumstances whereby rats and mice are repeatedly exposed to tasks in which they cannot learn.  Drugs have then been developed and then clinically validated that improve this learned helplessness in rodent models.

BRNI has developed a new model of learned helplessness using a spatial maze learning apparatus.  Using this depression model, BRNI scientists have demonstrated learned helpless not only on the maze task but also on a different task called instrumental conditioning.  Drugs developed and optimized at BRNI were then shown to reverse and/or prevent this learned helplessness in both tasks with efficacy equal to or greater than known antidepressants now in clinical use.  Insights gained at the synaptic level have again guided our development of such drugs that show promising potency and specificity for treating this psychiatric syndrome that affects so many members of our society.

Models of Memory Enhancement:  Discovery of the CBL-B Gene

In a study that illuminates how memory becomes impaired, the Institute recently identified a specific gene, cbl-b, which is a potential negative regulator of PKC pathways.  Transgenic mice in which this gene had been knocked out had markedly enhanced long-term memory.  While many such mutation-based interruptions of gene expression impair or obstruct long-term memory, none have actually significantly prolonged associative memory.  Brain synapses in the hippocampus of these mice also showed new capacity to undergo facilitatory changes that can contribute to memory storage.

This cbl-b gene regulates a protein that is biochemically linked to a number of signaling pathways and inhibits the molecular pathways necessary for storing long-term memories.  When the gene is deleted, these pathways are free to perform their function of transmitting memories from short to long-term storage.  These findings help identify where a breakdown in memory storage occurs, which molecular pathways are crucial to storing memories, and most importantly, the precise areas of the brain to target for further research.

Post-Traumatic Stress Disorder (PTSD)

Unlike civilian forms of PTSD, combat-related PTSD originates in unique environments under abnormal circumstances and is often difficult to treat.  Previous models of PTSD have been based on learning theories in which the cues associated with traumatic stress are thought to remind people of and elicit reactions to the stressful event.  It is upon these previous models that the less than successful treatments of combat-related PTSD have been based.  At BRNI, researchers have developed a rabbit model in which they assess the changing reactions not only to the cues associated with stress but to the stressful events themselves.  It is the over-reaction to stressful events that is a hallmark of post-traumatic stress disorder and of their model.

BRNI drug discovery research has also developed novel drugs that inhibit a critical enzyme, carbonic anhydrase, which regulates attention to minimize the extended context generality that frequently accompanies the PTSD syndrome.  Using this model, BRNI scientists have been able to screen drugs that show promising potential to ameliorate syndromes of PTSD.  Again, BRNI scientists are planning collaborations with Department of Defense scientists to optimize these drugs for treatment of civilian and military patients.