Perseveration is the continued response or persistent thought in the face of change that leads to diminished productivity. It is a notable feature of aging, Alzheimer's disease, drug abuse and various mental health disorders. The hippocampus receives influential input from the medial septum, predominantly from cholinergic and GABAergic neurons. Together, the hippocampus and medial septum are part of a system that fosters behavioral and cognitive flexibility, and as a result controls perseverative behaviors. However, the mechanism and neurons of the medial septum that are involved in this important function are unclear. Based on our previous results, it is hypothesized that the GABAergic medial septal neurons are critical for behavioral flexibility. Damage of the GABAergtic medial septal neurons is postulated to enhance proactive interference, resulting in perseveration. The proposed studies will test this hypothesis utilizing a novel GABAergic toxin and focusing on reversal learning.
Aims 1 and 2 will characterize the effects of this new GABAergic toxin in the medial septum using immunocytochemistry and in vivo microdialysis.
Aim 3 will examine the extent to which GABAergic damage enhances proactive interference in several forms of task switching.
Aim 4 will investigate the activation of the various MSDB neurons in reversal learning and rule shifting using activation of the immediate early gene, c-fos, and electrophysiology.
Aim 5 will test two possible mechanisms to account for the increased perseveration following GABAergic MSDB damage. The results of these studies will provide a better understanding of the mechanisms by which the septohippocampal system contributes to behavioral flexibility, perseveration and proactive interference. Because the medial septum and hippocampus are involved in a number of disorders with perseverative behaviors, the information gained from the proposed studies may lead to advances in their treatment and prevention.
Perseverative behaviors can be found in aging, drug abuse, Alzheimer's disease, schizophrenia, obsessive compulsive disorders and autism. Understanding the brain mechanisms involved in perseveration will advance our ability to treat or prevent a very debilitating component of these disorders.
|Roland, Jessica J; Stewart, Amanda L; Janke, Kellie L et al. (2014) Medial septum-diagonal band of Broca (MSDB) GABAergic regulation of hippocampal acetylcholine efflux is dependent on cognitive demands. J Neurosci 34:506-14|
|Roland, J J; Janke, K L; Servatius, R J et al. (2014) GABAergic neurons in the medial septum-diagonal band of Broca (MSDB) are important for acquisition of the classically conditioned eyeblink response. Brain Struct Funct 219:1231-7|
|Jiao, Xilu; Pang, Kevin C H; Beck, Kevin D et al. (2011) Avoidance perseveration during extinction training in Wistar-Kyoto rats: an interaction of innate vulnerability and stressor intensity. Behav Brain Res 221:98-107|
|Ricart, Thomas M; De Niear, Matthew A; Jiao, Xilu et al. (2011) Deficient proactive interference of eyeblink conditioning in Wistar-Kyoto rats. Behav Brain Res 216:59-65|
|Ricart, Thomas M; Jiao, Xilu; Pang, Kevin C H et al. (2011) Classical and instrumental conditioning of eyeblink responses in Wistar-Kyoto and Sprague-Dawley rats. Behav Brain Res 216:414-8|
|Pang, Kevin C H; Jiao, Xilu; Sinha, Swamini et al. (2011) Damage of GABAergic neurons in the medial septum impairs spatial working memory and extinction of active avoidance: effects on proactive interference. Hippocampus 21:835-46|
|Yoder, Ryan M; Pang, Kevin C H (2005) Involvement of GABAergic and cholinergic medial septal neurons in hippocampal theta rhythm. Hippocampus 15:381-92|
|Smith, H R; Pang, K C H (2005) Orexin-saporin lesions of the medial septum impair spatial memory. Neuroscience 132:261-71|
|Miller, Jonathan P; McAuley, J Devin; Pang, Kevin C H (2005) Spontaneous fos expression in the suprachiasmatic nucleus of young and old mice. Neurobiol Aging 26:1107-15|