Anatomy Commons^™

Prefrontal Cortical Microcircuits Bind Perception To Executive Control, Ioan Opris, Lucas Santos, Greg A. Gerhardt, Dong Song, Theodore W. Berger, Robert E. Hampson, Sam A. Deadwyler

Neuroscience Faculty Publications

During the perception-to-action cycle, our cerebral cortex mediates the interactions between the environment and the perceptual-executive systems of the brain. At the top of the executive hierarchy, prefrontal cortical microcircuits are assumed to bind perceptual and executive control information to guide goal-driven behavior. Here, we tested this hypothesis by comparing simultaneously recorded neuron firing in prefrontal cortical layers and the caudate-putamen of rhesus monkeys, trained in a spatial-versus-object, rule-based match-to-sample task. We found that during the perception and executive selection phases, cell firing in the localized prefrontal layers and caudate-putamen region exhibited similar location preferences on spatial-trials, but less on …

Striatal Glutamate Release In L-Dopa-Induced Dyskinetic Animals, Nina Nevalainen, Martin Lundblad, Greg A. Gerhardt, Ingrid Strömberg

Neuroscience Faculty Publications

L-DOPA-induced dyskinesia is a common side effect developed after chronic treatment with 3,4-dihydroxyphenyl-l-alanine (l-DOPA) in Parkinson's disease. The biological mechanisms behind this side effect are not fully comprehended although involvement of dopaminergic, serotonergic, and glutamatergic systems has been suggested. The present study utilizes in vivo amperometry to investigate the impact from unilateral 6-hydroxydopamine lesions and l-DOPA (4 mg/kg, including benserazide 15 mg/kg) -induced dyskinetic behavior on striatal basal extracellular glutamate concentration and potassium-evoked glutamate release in urethane-anesthetized rats. Recordings were performed before and after local L-DOPA application in the striatum. In addition, effects from the 5-HT_1A receptor agonist (2R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin …

Rod Microglia: Elongation, Alignment, And Coupling To Form Trains Across The Somatosensory Cortex After Experimental Diffuse Brain Injury, Jenna M. Ziebell, Samuel E. Taylor, Tuoxin Cao, Jordan L. Harrison, Jonathan Lifshitz

Neuroscience Faculty Publications

BACKGROUND: Since their discovery, the morphology of microglia has been interpreted to mirror their function, with ramified microglia constantly surveying the micro-environment and rapidly activating when changes occur. In 1899, Franz Nissl discovered what we now recognize as a distinct microglial activation state, microglial rod cells (Stäbchenzellen), which he observed adjacent to neurons. These rod-shaped microglia are typically found in human autopsy cases of paralysis of the insane, a disease of the pre-penicillin era, and best known today from HIV-1-infected brains. Microglial rod cells have been implicated in cortical 'synaptic stripping' but their exact role has remained unclear. This is …

Endogenous Dynorphin Protects Against Neurotoxin-Elicited Nigrostriatal Dopaminergic Neuron Damage And Motor Deficits In Mice, Qingshan Wang, Eun-Joo Shin, Xuan-Khanh Thi Nguyen, Quan Li, Jae-Hyung Bach, Guoying Bing, Won-Ki Kim, Hyoung-Chun Kim, Jau-Shyong Hong

Neuroscience Faculty Publications

BACKGROUND: The striato-nigral projecting pathway contains the highest concentrations of dynorphin in the brain. The functional role of this opioid peptide in the regulation of mesencephalic dopaminergic (DAergic) neurons is not clear. We reported previously that exogenous dynorphin exerts potent neuroprotective effects against inflammation-induced dopaminergic neurodegeneration in vitro. The present study was performed to investigate whether endogenous dynorphin has neuroprotective roles in vivo.

METHODS: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and methamphetamine (MA), two commonly used neurotoxins in rodent models of Parkinson's disease, were administered to wild-type (Dyn⁺/⁺) and prodynorphin-deficient mice (Dyn⁻/⁻). We examined dopaminergic neurotoxicity by using an automated video tracking system, HPLC, …

Eye Size At Birth In Prosimian Primates: Life History Correlates And Growth Patterns, Joshua R. Cummings, Magdalena N. Muchlinski, E. Christopher Kirk, Susan J. Rehorek, Valerie B. Deleon, Timothy D. Smith

Neuroscience Faculty Publications

BACKGROUND: Primates have large eyes relative to head size, which profoundly influence the ontogenetic emergence of facial form. However, growth of the primate eye is only understood in a narrow taxonomic perspective, with information biased toward anthropoids.

METHODOLOGY/PRINCIPAL FINDINGS: We measured eye and bony orbit size in perinatal prosimian primates (17 strepsirrhine taxa and Tarsius syrichta) to infer the extent of prenatal as compared to postnatal eye growth. In addition, multiple linear regression was used to detect relationships of relative eye and orbit diameter to life history variables. ANOVA was used to determine if eye size differed according to activity …

Maternal Separation Affects Dopamine Transporter Function In The Spontaneously Hypertensive Rat: An In Vivo Electrochemical Study, Jacqueline S. Womersley, Jennifer H. Hsieh, Lauriston A. Kellaway, Greg A. Gerhardt, Vivienne A. Russell

Neuroscience Faculty Publications

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder characterised by symptoms of inattention, impulsivity and hyperactivity. The spontaneously hypertensive rat (SHR) is a well-characterised model of this disorder and has been shown to exhibit dopamine dysregulation, one of the hypothesised causes of ADHD. Since stress experienced in the early stages of life can have long-lasting effects on behaviour, it was considered that early life stress may alter development of the dopaminergic system and thereby contribute to the behavioural characteristics of SHR. It was hypothesized that maternal separation would alter dopamine regulation by the transporter (DAT) in ways that distinguish SHR …

Anatomical Correlates To Nectar Feeding Among The Strepsirrhines Of Madagascar: Implications For Interpreting The Fossil Record, Magdalena N. Muchlinski, Jonathan M. G. Perry

Neuroscience Faculty Publications

One possible ecological scenario for the origin of primates is the archaic pollination and coevolution hypothesis. Its proponents contend that the consumption of nectar by some early primates and the resulting cross-pollination is an example of coevolution that drove adaptive radiations in some primates. This hypothesis is perhaps ecologically sound, but it lacks the morphology-behavior links that would allow us to test it using the fossil record. Here we attempt to identify cranial adaptations to nectar feeding among the strepsirrhines of Madagascar in order to provide such links. Many Malagasy strepsirrhines are considered effective cross-pollinators of the flowers they feed …

Targeted Over-Expression Of Glutamate Transporter 1 (Glt-1) Reduces Ischemic Brain Injury In A Rat Model Of Stroke, Brandon K. Harvey, Mikko Airavaara, Jason Michael Hinzman, Emily M. Wires, Matthew J. Chiocco, Douglas B. Howard, Hui Shen, Greg A. Gerhardt, Barry J. Hoffer, Yun Wang

Neuroscience Faculty Publications

Following the onset of an ischemic brain injury, the excitatory neurotransmitter glutamate is released. The excitotoxic effects of glutamate are a major contributor to the pathogenesis of a stroke. The aim of this study was to examine if overexpression of a glutamate transporter (GLT-1) reduces ischemic brain injury in a rat model of stroke. We generated an adeno-associated viral (AAV) vector expressing the rat GLT-1 cDNA (AAV-GLT1). Functional expression of AAV-GLT1 was confirmed by increased glutamate clearance rate in non-stroke rat brain as measured by in vivo amperometry. AAV-GLT1 was injected into future cortical region of infarction 3 weeks prior …

Differential Levels Of Glutamate Dehydrogenase 1 (Glud1) In Balb/C And C57bl/6 Mice And The Effects Of Overexpression Of The Glud1 Gene On Glutamate Release In Striatum, Kevin N. Hascup, Xiaodong Bao, Erin R. Hascup, Dongwei Hui, Wenhao Xu, Francois Pomerleau, Peter Huettl, Mary L. Michaelis, Elias K. Michaelis, Greg A. Gerhardt

Neuroscience Faculty Publications

We have previously shown that overexpression of the Glud1 (glutamate dehydrogenase 1) gene in neurons of C57BL/6 mice results in increased depolarization-induced glutamate release that eventually leads to selective neuronal injury and cell loss by 12 months of age. However, it is known that isogenic lines of Tg (transgenic) mice produced through back-crossing with one strain may differ in their phenotypic characteristics from those produced using another inbred mouse strain. Therefore, we decided to introduce the Glud1 transgene into the Balb/c strain that has endogenously lower levels of GLUD1 (glutamate dehydrogenase 1) enzyme activity in the brain as compared with …

Increased Mitochondrial Calcium Sensitivity And Abnormal Expression Of Innate Immunity Genes Precede Dopaminergic Defects In Pink1-Deficient Mice, Ravi S. Akundi, Zhenyu Huang, Joshua Eason, Jignesh D. Pandya, Lianteng Zhi, Wayne A. Cass, Patrick G. Sullivan, Hansruedi Büeler

Neuroscience Faculty Publications

BACKGROUND: PTEN-induced kinase 1 (PINK1) is linked to recessive Parkinsonism (EOPD). Pink1 deletion results in impaired dopamine (DA) release and decreased mitochondrial respiration in the striatum of mice. To reveal additional mechanisms of Pink1-related dopaminergic dysfunction, we studied Ca²⁺ vulnerability of purified brain mitochondria, DA levels and metabolism and whether signaling pathways implicated in Parkinson's disease (PD) display altered activity in the nigrostriatal system of Pink1⁻/⁻ mice.

METHODS AND FINDINGS: Purified brain mitochondria of ^Pink1⁻/⁻ mice showed impaired Ca²⁺ storage capacity, resulting in increased Ca²⁺ induced mitochondrial permeability transition (mPT) that was rescued by cyclosporine A. …

Lipopolysaccharide Animal Models For Parkinson's Disease, Mei Liu, Guoying Bing

Neuroscience Faculty Publications

Lipopolysaccharide (LPS), an endotoxin from Gram-negative bacteria, acts as a potent stimulator of microglia and has been used to study the inflammatory process in the pathogenesis of Parkinson's disease (PD) and anti-inflammatory therapy for PD treatment. Here, we review the growing body of literature on both in vitro and in vivo LPS PD models. Primary cell cultures from mesencephalic tissue were exposed to LPS in vitro; LPS was stereotaxically injected into the substantia nigra, striatum, or globus pallidus of brain or injected into the peritoneal cavity of the animal in vivo. In conclusion, the LPS PD models are summarized as …

Dopamine Neuron Stimulating Actions Of A Gdnf Propeptide, Luke H. Bradley, Josh Fuqua, April Richardson, Jadwiga Turchan-Cholewo, Yi Ai, Kristen A. Kelps, John D. Glass, Xiuquan He, Zhiming Zhang, Richard Grondin, O. Meagan Littrell, Peter Huettl, Francois Pomerleau, Don M. Gash, Greg A. Gerhardt

Neuroscience Faculty Publications

BACKGROUND: Neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF), have shown great promise for protection and restoration of damaged or dying dopamine neurons in animal models and in some Parkinson's disease (PD) clinical trials. However, the delivery of neurotrophic factors to the brain is difficult due to their large size and poor bio-distribution. In addition, developing more efficacious trophic factors is hampered by the difficulty of synthesis and structural modification. Small molecules with neurotrophic actions that are easy to synthesize and modify to improve bioavailability are needed.

METHODS AND FINDINGS: Here we present the neurobiological actions of dopamine …

Striatal Neuroinflammation Promotes Parkinsonism In Rats, Dong-Young Choi, Mei Liu, Randy L. Hunter, Wayne A. Cass, Jignesh D. Pandya, Patrick G. Sullivan, Eun-Joo Shin, Hyoung-Chun Kim, Don M. Gash, Guoying Bing

Neuroscience Faculty Publications

BACKGROUND: Sporadic Parkinson's disease (PD) is a progressive neurodegenerative disorder with unknown cause, but it has been suggested that neuroinflammation may play a role in pathogenesis of the disease. Neuroinflammatory component in process of PD neurodegeneration was proposed by postmortem, epidemiological and animal model studies. However, it remains unclear how neuroinflammatory factors contribute to dopaminergic neuronal death in PD.

FINDINGS: In this study, we analyzed the relationship among inducible nitric oxide synthase (iNOS)-derived NO, mitochondrial dysfunction and dopaminergic neurodegeneration to examine the possibility that microglial neuroinflammation may induce dopaminergic neuronal loss in the substantia nigra. Unilateral injection of lipopolysaccharide (LPS) …

Pioglitazone Inhibition Of Lipopolysaccharide-Induced Nitric Oxide Synthase Is Associated With Altered Activity Of P38 Map Kinase And Pi3k/Akt, Bin Xing, Tao Xin, Randy Lee Hunter, Guoying Bing

Neuroscience Faculty Publications

BACKGROUND: Previous studies have suggested that peroxisome proliferator activated receptor-gamma (PPAR-gamma)-mediated neuroprotection involves inhibition of microglial activation and decreased expression and activity of inducible nitric oxide synthase (iNOS); however, the underlying molecular mechanisms have not yet been well established. In the present study we explored: (1) the effect of the PPAR-gamma agonist pioglitazone on lipopolysaccharide (LPS)-induced iNOS activity and nitric oxide (NO) generation by microglia; (2) the differential role of p38 mitogen-activated protein kinase (p38 MAPK), c-Jun NH(2)-terminal kinase (JNK), and phosphoinositide 3-kinase (PI3K) on LPS-induced NO generation; and (3) the regulation of p38 MAPK, JNK, and PI3K by pioglitazone. …

Prenatal Cocaine Exposure Alters Alpha2 Receptor Expression In Adolescent Rats, Rosemarie M. Booze, David R. Wallace, Janelle M. Silvers, Barbara J. Strupp, Diane M. Snow, Charles F. Mactutus

Neuroscience Faculty Publications

BACKGROUND: Prenatal cocaine exposure produces attentional deficits which to persist through early childhood. Given the role of norepinephrine (NE) in attentional processes, we examined the forebrain NE systems from prenatal cocaine exposed rats. Cocaine was administered during pregnancy via the clinically relevant intravenous route of administration. Specifically, we measured alpha2-adrenergic receptor (alpha2-AR) density in adolescent (35-days-old) rats, using [3H]RX821002 (5 nM).

RESULTS: Sex-specific alterations of alpha2-AR were found in the hippocampus and amygdala of the cocaine-exposed animals, as well as an upregulation of alpha2-AR in parietal cortex.

CONCLUSION: These data suggest that prenatal cocaine exposure results in a persistent alteration …

Cyclooxygenase-2 Mediates Microglial Activation And Secondary Dopaminergic Cell Death In The Mouse Mptp Model Of Parkinson's Disease, Rattanavijit Vijitruth, Mei Liu, Dong-Young Choi, Xuan V. Nguyen, Randy L. Hunter, Guoying Bing

Neuroscience Faculty Publications

BACKGROUND: Accumulating evidence suggests that inflammation plays an important role in the progression of Parkinson's disease (PD). Among many inflammatory factors found in the PD brain, cyclooxygenase (COX), specifically the inducible isoform, COX-2, is believed to be a critical enzyme in the inflammatory response. Induction of COX-2 is also found in an experimental model of PD produced by administration of 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

METHOD: COX-2-deficient mice or C57BL/6 mice were treated with MPTP to investigate the effects of COX-2 deficiency or by using various doses of valdecoxib, a specific COX-2 inhibitor, which induces inhibition of COX-2 on dopaminergic neuronal toxicity and …