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.
|Fragale, Jennifer E C; Khariv, Veronika; Gregor, Danielle M et al. (2016) Dysfunction in amygdala-prefrontal plasticity and extinction-resistant avoidance: A model for anxiety disorder vulnerability. Exp Neurol 275 Pt 1:59-68|
|Janke, Kellie L; Cominski, Tara P; Kuzhikandathil, Eldo V et al. (2015) Investigating the Role of Hippocampal BDNF in Anxiety Vulnerability Using Classical Eyeblink Conditioning. Front Psychiatry 6:106|
|Jiao, Xilu; Beck, Kevin D; Myers, Catherine E et al. (2015) Altered activity of the medial prefrontal cortex and amygdala during acquisition and extinction of an active avoidance task. Front Behav Neurosci 9:249|
|Pang, Kevin C H; Sinha, Swamini; Avcu, Pelin et al. (2015) Long-lasting suppression of acoustic startle response after mild traumatic brain injury. J Neurotrauma 32:801-10|
|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|
|Cominski, Tara P; Jiao, Xilu; Catuzzi, Jennifer E et al. (2014) The role of the hippocampus in avoidance learning and anxiety vulnerability. Front Behav Neurosci 8:273|
|Jiao, Xilu; Beck, Kevin D; Stewart, Amanda L et al. (2014) Effects of psychotropic agents on extinction of lever-press avoidance in a rat model of anxiety vulnerability. Front Behav Neurosci 8:322|
|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|
|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|
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