IU Indianapolis ScholarWorks :: Browsing by Author "McKinzie, David L."

Browsing by Author "McKinzie, David L."

Now showing 1 - 10 of 12

Aberrant Neural Activity in Cortico-Striatal-Limbic Circuitry Underlies Behavioral Deficits in a Mouse Model of Neurofibromatosis Type 1
(2022-05) Drozd, Hayley Paulina; McKinzie, David L.; Clapp, D. Wade; Shekhar, Anantha; Lukkes, Jodi L.; Lapish, Christopher L.; Block, Michelle L.
Nearly 18% of children are diagnosed with developmental disabilities. Autism spectrum disorders (ASDs) and attention deficit hyperactivity disorder (ADHD) are increasingly common developmental disabilities, but neither is well understood. ADHD and ASD are both prevalent in the genetic disorder Neurofibromatosis type 1 (NF1) which impairs the Ras-MAPK/ERK pathway through mutation of the neurofibromin gene (NF1+/−). More broadly, syndromic forms of developmental disorders are often caused by mutations of proteins in pathways interconnected with Ras including TSC1/2, FMR1, and SynGAP. Of NF1 patients, around 30-50% are diagnosed with ASDs and more than 60% with ADHD. These studies are the first to show that male mice haploinsufficient for the Nf1 gene (Nf1+/−) exhibit deficits in behavioral inhibition in multiple contexts, a key feature of ADHD. They exhibit hyperactivity and impulsivity in an open field, delay discounting task, and cliff avoidance reaction test, rescuable through treatment with the clinically effective ADHD drug, guanfacine (α2A adrenergic receptor agonist). Previous experiments in our lab identified social deficits including deficits in consolidation of social memory. Using optogenetics and awake behaving electrode recordings, we explored the role of the cortico-striatal-limbic circuitry in impulsivity and in social deficits in male Nf1+/− mice. Manipulation of the prefrontal cortex, nucleus accumbens, or basolateral amygdala through optogenetics rescued social deficits. These studies are the first to record brain activity in a preclinical model of NF1 during impulsive behavior, finding broad spectrum changes across slow, delta, theta, and gamma oscillatory frequencies and decreased synchrony of the prefrontal cortex and nucleus accumbens during a delay discounting task. Overall, Nf1+/− male mice with deletion of a single NF1 gene recapitulate cognitive phenotypes of NF1 patients and are a useful model system to identify alterations in neural circuitry associated with ASD and ADHD.
Bassoon contributes to tau-seed propagation and neurotoxicity
(Springer Nature, 2022) Martinez, Pablo; Patel, Henika; You, Yanwen; Jury, Nur; Perkins, Abigail; Lee-Gosselin, Audrey; Taylor, Xavier; You, Yingjian; Di Prisco, Gonzalo Viana; Huang, Xiaoqing; Dutta, Sayan; Wijeratne, Aruna B.; Redding-Ochoa, Javier; Shahid, Syed Salman; Codocedo, Juan F.; Min, Sehong; Landreth, Gary E.; Mosley, Amber L.; Wu, Yu-Chien; McKinzie, David L.; Rochet, Jean-Christophe; Zhang, Jie; Atwood, Brady K.; Troncoso, Juan; Lasagna-Reeves, Cristian A.; Anatomy, Cell Biology and Physiology, School of Medicine
Tau aggregation is a defining histopathological feature of Alzheimer’s disease and other tauopathies. However, the cellular mechanisms involved in tau propagation remain unclear. Here, we performed an unbiased quantitative proteomic study to identify proteins that specifically interact with this tau seed. We identified Bassoon (BSN), a presynaptic scaffolding protein, as an interactor of the tau seed isolated from a mouse model of tauopathy, and from Alzheimer’s disease and progressive supranuclear palsy postmortem samples. We show that BSN exacerbates tau seeding and toxicity in both mouse and Drosophila models for tauopathy, and that BSN downregulation decreases tau spreading and overall disease pathology, rescuing synaptic and behavioral impairments and reducing brain atrophy. Our findings improve the understanding of how tau seeds can be stabilized by interactors such as BSN. Inhibiting tau-seed interactions is a potential new therapeutic approach for neurodegenerative tauopathies.
Characterizing Effects of Sphingosine-1-Phosphate Receptor 1 Activation in Subtypes of Central Amygdala Neurons and Effects of Prenatal Methadone Exposure on Motor Cortex Neurons in Mice
(2021-04) Mork, Briana E.; Atwood, Brady K.; Sheets, Patrick L.; Cummins, Theodore R.; Fehrenbacher, Jill C.; McKinzie, David L.
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that mediates a wide spectrum of biological processes including apoptosis, immune response and inflammation. S1P receptor (S1PR) ligands have been utilized as an effective immunosuppressant, treatment in multiple sclerosis and studied as a treatment for pain. The primary cellular response to S1P is thought to be elicited through S1PR type 1 (S1PR1). My first goal was to understand how S1PR1 signaling affects neuronal excitability in the central amygdala (CeA), a supraspinal node of the descending pain pathway. The CeA is made up of a heterogenous population of neurons which form complex local and long-range circuits. The central lateral amygdala (CeL) consists of two major populations of inhibitory neurons identified by expression of the peptides somatostatin (Sst) and protein kinase Cδ (PKCδ). Sst neurons have been shown to maintain control over local circuits within the CeL and play a critical role in pain modulation. I utilized transgenic breeding strategies to fluorescently label Sst-expressing CeL neurons for whole-cell electrophysiology in acute brain slice. This strategy allowed me to study the effects of S1PR1 agonist SEW2871 and S1PR1 antagonist NIBR on the cellular physiology of CeL Sst neurons. My findings reveal intrinsically distinct subtypes of CeL Sst neurons that are uniquely affected by S1PR1 activation, which may have implications for how S1P alters supraspinal pain pathways. My second goal was to assess the physiology of motor cortex neurons in mice exposed to prenatal methadone. Methadone is a synthetic μ-opioid agonist used for opioid maintenance therapy and chronic pain management. Methadone treatment for opioid use disorder in pregnant women can result in structural changes within the brain of their offspring causing and developmental delays to their children, including poorer motor performance. Using a mouse model of prenatal methadone exposure (PME), whole-cell electrophysiology, and analyses of cellular morphology, I elucidated the effects of PME on primary motor cortex (M1) output layer 5 (L5) neurons, which encompass the major cortical output pathway for motor control. My findings provide the first evidence that PME disrupts neuronal firing, subthreshold properties, and strength of local inputs onto M1 L5 neurons in prepubescent mice.
Converging Effects of Chronic Pain and Binge Alcohol Consumption on Corticostriatal Neurons and the Effects of Acute Alcohol Exposure on the Medial Prefrontal Cortex
(2024-07) Yin, Yuexi; Atwood, Brady K.; Baucum, AJ; Hopf, Woody; McKinzie, David L.; Sheets, Patrick L.
Chronic pain and alcohol use disorder (AUD) are highly comorbid, but whether the two conditions share common brain pathways is unclear. Prior work shows that the anterior insular cortex (AIC) is involved in both chronic pain and alcohol use disorder. However, circuit-specific changes elicited by the combination of pain and alcohol use remain understudied. The goal of this work was to elucidate the converging effects of binge alcohol consumption and chronic pain on AIC neurons that send projections to the dorsolateral striatum (DLS). Here, we used the Drinking-in-the-Dark paradigm to model binge-like alcohol drinking in mice that underwent spared nerve injury (SNI). We found that SNI male mice with no prior alcohol exposure consumed less alcohol compared to sham mice. Electrophysiological analyses showed that AIC-DLS neurons from SNI-alcohol male mice displayed increased neuronal excitability and increased frequency of miniature excitatory postsynaptic currents. However, mice exposed to alcohol prior to SNI consumed similar amounts of alcohol compared to sham mice following SNI. Together, our data suggest that the pain and alcohol interaction can sensitize the AIC-DLS circuit in mice, which may be critical in understanding how chronic pain alters motivated behaviors associated with alcohol. My second goal was to assess the acute pharmacological effects of alcohol on prodynorphin-expressing neurons in the prelimbic cortex (PLPdyn+), a subregion of the medial prefrontal cortex (mPFC). Kappa opioid receptor (KOR) system dysregulation contributes to alcohol addiction. Prodynorphin (Pdyn) is the precursor peptide to the endogenous opioid ligand for KORs. Early studies demonstrated that acute alcohol exposure elevates Pdyn mRNA expression in the mPFC. However, its functional effects on Pdyn-expressing neurons are not known. Here, we used whole-cell patch-clamp electrophysiology in acute brain slices and glutamate-uncaging via laser scanning photo to map local excitatory and inhibitory inputs onto PL neurons. We found that acute alcohol increases local inhibitory inputs to both layer 2/3 PLPdyn+ and PLPdyn- neurons but has no effect on excitatory inputs. Under untreated conditions, PLPdyn+ neurons show stronger local excitatory inputs compared to PLPdyn- neurons. Overall, these data suggest that acute alcohol intoxication inhibits intracortical circuit of PL neurons regardless of neuronal subtypes.
Dissecting the Effects of Different Pain Modalities and Oxycodone on Prodynorphin Expressing Neurons in the Mouse Prelimbic Cortex
(2022-11) Zhou, Shudi; Atwood, Brady K.; Sheets, Patrick L.; McKinzie, David L.; Truitt, William A.; Jin, Xiaoming
Currently, changes to endogenous opioid circuits in various pain modalities, including surgical and neuropathic pain, remain unclear. Dynorphin, which is released by prodynorphin-expressing neurons (Pdyn+ neurons), is the endogenous opioid ligand to kappa opioid receptors (KOR). Moreover, a recent study has shown an increase in prodynorphin (Pdyn) mRNA expression in the prelimbic cortex (PL) in a mouse model of chronic pain. However, alterations in the activity of PL Pdyn-expressing neurons (PLPdyn+ neurons) in postoperative and chronic pain have never been explored. Firstly, I found that the population of PLPdyn+ neurons consists of both pyramidal and inhibitory subtypes. Secondly, I found that one day after surgical incision of the mouse hind paw, the excitability of pyramidal PLPdyn+ neurons was increased in both male and female mice, while the excitability of inhibitory PLPdyn+ neurons was unchanged. However, when postoperative pain behavior subsided, inhibitory PLPdyn+ neurons were hyperexcitable in male mice, while pyramidal PLPdyn+ neurons were hypoexcitable in female mice. Lastly, I dissected electrophysiological changes to PLPdyn+ neurons in the spared nerve injury (SNI) model of chronic neuropathic pain. At both early and late stages of SNI pain development, increased excitability of pyramidal PLPdyn+ neurons was detected in both male and female mice. However, in both male and female mice, the excitability of inhibitory PLPdyn+ neurons decreased 3 days after SNI but was conversely increased when measured 14 days after SNI. My findings suggest that different subtypes of PLPdyn+ neurons manifest distinct alterations in the development of different pain modalities in a sex-specific manner.
Effects of naltrexone and LY255582 on ethanol maintenance, seeking, and relapse responding by alcohol-preferring (P) rats
(Elsevier B.V., 2012-02) Dhaher, Ronnie; Toalston, Jamie E.; Hauser, Sheketha R.; Bell, Richard L.; McKinzie, David L.; McBride, William J.; Rodd, Zachary A.; Department of Psychiatry, IU School of Medicine
Research indicates opioid antagonists can reduce alcohol drinking in rodents. However, tests examining the effects of opioid antagonists on ethanol seeking and relapse behavior have been limited. The present study examined the effects of two opioid antagonists on ethanol maintenance, seeking, and relapse responding by alcohol-preferring (P) rats. Adult P rats were self-trained in two-lever operant chambers to self-administer 15% (vol/vol) ethanol on a fixed-ratio 5 (FR5) versus water on a FR1 concurrent schedule of reinforcement in daily 1-h sessions. After 10 weeks, rats underwent extinction training, followed by 2 weeks in their home cages. Rats were then returned to the operant chambers without ethanol or water to measure responses on the ethanol and water levers for four sessions. After a subsequent 2 weeks in the home cage, without access to ethanol, rats were returned to the operant chambers with ethanol and water available. Effects of antagonists on maintenance responding were tested after several weeks of daily 1-h sessions. Naltrexone (NAL; 1–10 mg/kg, subcutaneously [s.c.]; n = 8/dose), LY255582 (LY; 0.03–1 mg/kg, s.c.; n = 8/dose), or vehicle were injected 30 min before the first session (in the absence of ethanol), following 2 weeks in their home cages, and for four consecutive sessions of ethanol self-administration under maintenance and relapse conditions. Both NAL and LY reduced responses on the ethanol lever without any fluids present, and ethanol self-administration under relapse and on-going drinking conditions, with LY being more potent than NAL. Both NAL and LY were less effective in reducing responding in the absence of ethanol than in reducing ethanol self-administration. Overall, the results indicate that the opioid system is involved in mediating ethanol seeking, and ethanol self-administration under relapse and on-going alcohol drinking, but that different neurocircuits may underlie these behaviors.
Further Characterization of Multi-Organ DEARE and Protection by 16,16 Dimethyl Prostaglandin E2 in a Mouse Model of the Hematopoietic Acute Radiation Syndrome
(BioOne, 2023) Wu, Tong; Pelus, Louis M.; Plett, P. Artur; Sampson, Carol H.; Chua, Hui Lin; Fisher, Alexa; Feng, Hailin; Liu, Liqiong; Li, Hongge; Ortiz, Miguel; Chittajallu, Supriya; Luo, Qianyi; Bhatwadekar, Ashay D.; Meyer, Timothy B.; Zhang, Xin; Zhou, Daohong; Fischer, Kathryn D.; McKinzie, David L.; Miller, Steven J.; Orschell, Christie M.; Medicine, School of Medicine
Survivors of acute radiation exposure suffer from the delayed effects of acute radiation exposure (DEARE), a chronic condition affecting multiple organs, including lung, kidney, heart, gastrointestinal tract, eyes, and brain, and often causing cancer. While effective medical countermeasures (MCM) for the hematopoietic-acute radiation syndrome (H-ARS) have been identified and approved by the FDA, development of MCM for DEARE has not yet been successful. We previously documented residual bone marrow damage (RBMD) and progressive renal and cardiovascular DEARE in murine survivors of H-ARS, and significant survival efficacy of 16,16-dimethyl prostaglandin E2 (dmPGE2) given as a radioprotectant or radiomitigator for H-ARS. We now describe additional DEARE (physiological and neural function, progressive fur graying, ocular inflammation, and malignancy) developing after sub-threshold doses in our H-ARS model, and detailed analysis of the effects of dmPGE2 administered before (PGE-pre) or after (PGE-post) lethal total-body irradiation (TBI) on these DEARE. Administration of PGE-pre normalized the twofold reduction of white blood cells (WBC) and lymphocytes seen in vehicle-treated survivors (Veh), and increased the number of bone marrow (BM) cells, splenocytes, thymocytes, and phenotypically defined hematopoietic progenitor cells (HPC) and hematopoietic stem cells (HSC) to levels equivalent to those in non-irradiated age-matched controls. PGE-pre significantly protected HPC colony formation ex vivo by >twofold, long term-HSC in vivo engraftment potential up to ninefold, and significantly blunted TBI-induced myeloid skewing. Secondary transplantation documented continued production of LT-HSC with normal lineage differentiation. PGE-pre reduced development of DEARE cardiovascular pathologies and renal damage; prevented coronary artery rarefication, blunted progressive loss of coronary artery endothelia, reduced inflammation and coronary early senescence, and blunted radiation-induced increase in blood urea nitrogen (BUN). Ocular monocytes were significantly lower in PGE-pre mice, as was TBI-induced fur graying. Increased body weight and decreased frailty in male mice, and reduced incidence of thymic lymphoma were documented in PGE-pre mice. In assays measuring behavioral and cognitive functions, PGE-pre reduced anxiety in females, significantly blunted shock flinch response, and increased exploratory behavior in males. No effect of TBI was observed on memory in any group. PGE-post, despite significantly increasing 30-day survival in H-ARS and WBC and hematopoietic recovery, was not effective in reducing TBI-induced RBMD or any other DEARE. In summary, dmPGE2 administered as an H-ARS MCM before lethal TBI significantly increased 30-day survival and ameliorated RBMD and multi-organ and cognitive/behavioral DEARE to at least 12 months after TBI, whereas given after TBI, dmPGE2 enhances survival from H-ARS but has little impact on RBMD or other DEARE.
Genetic Background and Sex: Impact on Generalizability of Research Findings in Pharmacology Studies
(Springer, 2020) Sukoff Rizzo, Stacey J.; McTighe, Stephanie; McKinzie, David L.; Pharmacology and Toxicology, School of Medicine
Animal models consisting of inbred laboratory rodent strains have been a powerful tool for decades, helping to unravel the underpinnings of biological problems and employed to evaluate potential therapeutic treatments in drug discovery. While inbred strains demonstrate relatively reliable and predictable responses, using a single inbred strain alone or as a background to a mutation is analogous to running a clinical trial in a single individual and their identical twins. Indeed, complex etiologies drive the most common human diseases, and a single inbred strain that is a surrogate of a single genome, or data generated from a single sex, is not representative of the genetically diverse patient populations. Further, pharmacological and toxicology data generated in otherwise healthy animals may not translate to disease states where physiology, metabolism, and general health are compromised. The purpose of this chapter is to provide guidance for improving generalizability of preclinical studies by providing insight into necessary considerations for introducing systematic variation within the study design, such as genetic diversity, the use of both sexes, and selection of appropriate age and disease model. The outcome of implementing these considerations should be that reproducibility and generalizability of significant results are significantly enhanced leading to improved clinical translation.
Microglial knockdown does not affect acute withdrawal but delays analgesic tolerance from oxycodone in male and female C57BL/6J mice
(Frontiers Media, 2022-12-16) El Jordi, Omar; Fischer, Kathryn D.; Meyer, Timothy B.; Atwood, Brady K.; Oblak, Adrian L.; Pan, Raymond W.; McKinzie, David L.; Pharmacology and Toxicology, School of Medicine
Opioid Use Disorder (OUD) affects approximately 8%–12% of the population. In dependent individuals, abrupt cessation of opioid taking results in adverse withdrawal symptoms that reinforce drug taking behavior. Considerable unmet clinical need exists for new pharmacotherapies to treat opioid withdrawal as well as improve long-term abstinence. The neuroimmune system has received much scientific attention in recent years as a potential therapeutic target to combat various neurodegenerative and psychiatric disorders including addiction. However, the specific contribution of microglia has not been investigated in oxycodone dependence. Chronic daily treatment with the CSF1R inhibitor Pexidartinib (PLX3397) was administered to knockdown microglia expression and evaluate consequences on analgesia and on naloxone induced withdrawal from oxycodone. In vivo results indicated that an approximately 40% reduction in brain IBA1 staining was achieved in the PLX treatment group, which was associated with a delay in the development of analgesic tolerance to oxycodone and maintained antinociceptive efficacy. Acute withdrawal behavioral symptoms, brain astrocyte expression, and levels of many neuroinflammatory markers were not affected by PLX treatment. KC/GRO (also known as CXCL1) was significantly enhanced in the somatosensory cortex in oxycodone‐treated mice receiving PLX. Microglial knock-down did not affect the expression of naloxoneinduced opioid withdrawal but affected antinociceptive responsivity. The consequences of increased KC/GRO expression within the somatosensory cortex due to microglial reduction during opioid dependence are unclear but may be important for neural pathways mediating opioid‐induced analgesia.
Prostaglandin-Mediated Reinstatement of Drug Taking After Alcohol Drinking by Female Adolescent Rats
(2022-04) Kline, Hannah L.; Engleman, Eric A.; Atwood, Brady K.; McKinzie, David L.; Truitt, William A.; Yamamoto, Bryan K.
Adolescent alcohol abuse is a global problem that initiates lifelong addiction. Alcohol use during adolescence is associated with subsequent Meth dependence in humans. Specifically, female adolescents are particularly vulnerable to serial alcohol and Meth use. However, it is unknown if prior voluntary alcohol drinking impacts subsequent Meth-taking in female adolescent rats. Both alcohol and Meth increase the prostaglandin synthesis enzyme cyclooxygenase-2 (COX-2) in the brain but the effect of serial exposure to alcohol and Meth on COX-2 has not been determined. The first study uses a novel method of serial voluntary alcohol drinking and Meth self-administration in female adolescent rats to model human patterns of co-abuse. Prior alcohol drinking did not affect subsequent Meth self-administration, but it reduced the cue-primed reinstatement of Methseeking after abstinence from Meth. Rats with a history of adolescent alcohol drinking also had increased COX-2 in the dorsal striatum, regardless of subsequent Meth selfadministration. These findings demonstrate that a history of adolescent alcohol drinking does not alter Meth self-administration but persistently reduces cue-primed Meth seeking and increases COX-2 after prolonged abstinence from alcohol. To further examine the role of COX-2 in alcohol drinking, the second study found that adolescent alcohol drinking not only increased COX-2 after four weeks of alcohol abstinence, but also increased endothelin-1 (ET-1) and prostaglandin E2 (PGE2) in the dorsal striatum. Furthermore, adolescent alcohol drinking increased alcohol drinking after abstinence, and this increase was attenuated by treatment with the COX-2 inhibitor nimesulide during abstinence. Antagonism of the interaction between PGE2 and its receptor 1 (EP1) also attenuated the increase in relapse drinking and restored alcohol drinking to the rate of alcohol naïve rats. Overall, these experiments identified a prostaglandin-mediated mechanism that is a putative target for the treatment of alcohol relapse following abstinence in individuals with a history of adolescent alcohol abuse.

Browsing by Author "McKinzie, David L."

Results Per Page

Sort Options