Kolb, Bryanhttps://hdl.handle.net/10133/45752024-03-29T08:16:05Z2024-03-29T08:16:05Z111Growth of malignant extracranial tumors alters microRNAome in the prefrontal cortext of TumorGraft miceKovalchuk, AnnaIlnytskyy, YaroslavRodriquez-Juarez, RocioKatz, AmandaSidransky, DavidKolb, BryanKovalchuk, Olgahttps://hdl.handle.net/10133/52782020-05-26T22:50:39Z2017-01-01T00:00:00Zdc.title: Growth of malignant extracranial tumors alters microRNAome in the prefrontal cortext of TumorGraft mice
dc.contributor.author: Kovalchuk, Anna; Ilnytskyy, Yaroslav; Rodriquez-Juarez, Rocio; Katz, Amanda; Sidransky, David; Kolb, Bryan; Kovalchuk, Olga
dc.description.abstract: A wide array of central nervous system complications, neurological deficits, and cognitive impairments occur and persist as a result of systemic cancer and cancer treatments. This condition is known as chemo brain and it affects over half of cancer survivors. Recent studies reported that cognitive impairments manifest before chemotherapy and are much broader than chemo brain alone, thereby adding in tumor brain as a component. The molecular mechanisms of chemo brain are underinvestigated, and the mechanisms of tumor brain have not been analyzed at all. The frequency and timing, as well as the long-term persistence, of chemo brain and tumor brain suggest they may be epigenetic in nature. MicroRNAs, small, single-stranded non-coding RNAs, constitute an important part of the cellular epigenome and are potent regulators of gene expression. miRNAs are crucial for brain development and function, and are affected by a variety of different stresses, diseases and conditions. However, nothing is known about the effects of extracranial tumor growth or chemotherapy agents on the brain microRNAome. We used the well-established TumorGraft TM mouse models of triple negative (TNBC) and progesterone receptor positive (PR+BC) breast cancer, and profiled global microRNAome changes in tumor-bearing mice upon chemotherapy, as compared to untreated tumor-bearing mice and intact mice. Our analysis focused on the prefrontal cortex (PFC), based on its roles in memory, learning, and executive functions, and on published data showing the PFC is a target in chemo brain. This is the first study showing that tumor presence alone significantly impacted the small RNAome of PFC tissues. Both tumor growth and chemotherapy treatment affected the small RNAome and altered levels of miRNAs, piRNAs, tRNAs, tRNA fragments and other molecules involved in post-transcriptional regulation of gene expression. Amongst those, miRNA changes were the most pronounced, involving several miRNA families, such as the miR-200 family and miR-183/96/182 cluster; both were deregulated in tumor-bearing and chemotherapy-treated animals. We saw that miRNA deregulation was associated with altered levels of brain-derived neurotrophic factor (BDNF), which plays an important role in cognition and memory and is one of the known miRNA targets. BDNF downregulation has been associated with an array of neurological conditions and could be one of the mechanisms underlying tumor brain and chemo brain. In the future our study could serve as a roadmap for further analysis of cancer and chemotherapy’s neural side effects, and differentially expressed miRNAs should be explored as potential tumor brain and chemo brain biomarkers.
dc.description: Sherpa Romeo blue journal. Open access article. Creative Commons Attribution 3.0 License (CC BY 3.0) applies
2017-01-01T00:00:00ZLiver irradiation causes distal bystander effects in the rat brain and affects animal behaviorKovalchuk, AnnaMychasiuk, RichelleMuhammad, ArifHossain, ShakhawatIlnytskyy, SlavaGhose, AbhijitKirby, CharlesGhasroddashti3, EsmaeelKovalchuk, OlgaKolb, Bryanhttps://hdl.handle.net/10133/52732020-05-27T01:25:33Z2016-01-01T00:00:00Zdc.title: Liver irradiation causes distal bystander effects in the rat brain and affects animal behavior
dc.contributor.author: Kovalchuk, Anna; Mychasiuk, Richelle; Muhammad, Arif; Hossain, Shakhawat; Ilnytskyy, Slava; Ghose, Abhijit; Kirby, Charles; Ghasroddashti3, Esmaeel; Kovalchuk, Olga; Kolb, Bryan
dc.description.abstract: Radiation therapy can not only produce effects on targeted organs, but can also influence shielded bystander organs, such as the brain in targeted liver irradiation. The brain is sensitive to radiation exposure, and irradiation causes significant neurocognitive deficits, including deficits in attention, concentration, memory, and executive and visuospatial functions. The mechanisms of their occurrence are not understood, although they may be related to the bystander effects. We analyzed the induction, mechanisms, and behavioural repercussions of bystander effects in the brain upon liver irradiation in a well-established rat model. Here, we show for the first time that bystander effects occur in the prefrontal cortex and hippocampus regions upon liver irradiation, where they manifest as altered gene expression and somewhat increased levels of fH2AX. We also report that bystander effects in the brain are associated with neuroanatomical and behavioural changes, and are more pronounced in females than in males.
dc.description: Sherpa Romeo blue journal. Open access: Creative Commons Attribution 3.0 License (CC BY 3.0) applies.
2016-01-01T00:00:00ZCorticosterone response to gestational stress and postpartum memory function in miceJafari, ZahraMehla, JogenderAfrashteh, NavvabKolb, BryanMohajerani, Majid H.https://hdl.handle.net/10133/52512021-01-13T15:02:43Z2017-01-01T00:00:00Zdc.title: Corticosterone response to gestational stress and postpartum memory function in mice
dc.contributor.author: Jafari, Zahra; Mehla, Jogender; Afrashteh, Navvab; Kolb, Bryan; Mohajerani, Majid H.
dc.description.abstract: Maternal stress is a common adversity during pregnancy. Gestational corticosterone alternations are thought to contribute to the etiology of postpartum behavioral disturbances. However, the impact of stress during pregnancy, in particular noise exposure, on gestational corticosterone fluctuations and spatial cognition in postpartum mice has not been fully understood yet. We hypothesized that noise exposure during pregnancy negatively affects gestational corticosterone levels and postpartum memory function in the dams similar to the physical stressors. Pregnant C57BL/6 mice were randomly assigned to either one of two stress conditions or a control condition. The noise stress (NS) was induced by presenting a loud intermittent 3000 Hz frequency on gestational days (GDs) 12, 14, and 16 for 24 hours, whereas the physical stress (PS) consisted of restraint and exposure to an elevated platform on GDs 12–16. Plasma corticosterone level was collected on GDs 11 and 17, and Morris water task (MWT) was carried out 30 days after parturition. Compared to the control group, the level of corticosterone in the stressed groups was significantly increased on GD17 relative to GD11. Significantly longer swim time and lower swim speed were observed in both stressed groups relative to the control group. Probe time was significantly shorter in the NS group than the other groups. The delta corticosterone level was significantly correlated with the swim time as well as the probe time in the three groups. Given the results, the adverse effects of gestational noise exposure on the hypothalamic pituitary-adrenal (HPA) axis activation and postpartum spatial learning and memory function were as large as/ or a bit stronger than the physical stresses. The findings suggest the significance of conservation against loud noise exposure in daily living, as well as need to further notice to the different aspects of gestational stress in mothers’ behavior like offspring.
dc.description: Open access; distributed under the terms of the Creative Commons Attribution License
2017-01-01T00:00:00ZProfound and sexually dimorphic effects of clinically-relevant low dose scatter irradiation on the brain and behaviorKovalchuk, AnnaMychasiuk, RichelleMuhammad, ArifHossain, ShakhawatIlnytskyy, YaroslavGhose, AbhijitKirkby, CharlesGhasroddashti, EsmaeelKolb, BryanKovalchuk, Olgahttps://hdl.handle.net/10133/47272016-11-23T06:04:41Z2016-01-01T00:00:00Zdc.title: Profound and sexually dimorphic effects of clinically-relevant low dose scatter irradiation on the brain and behavior
dc.contributor.author: Kovalchuk, Anna; Mychasiuk, Richelle; Muhammad, Arif; Hossain, Shakhawat; Ilnytskyy, Yaroslav; Ghose, Abhijit; Kirkby, Charles; Ghasroddashti, Esmaeel; Kolb, Bryan; Kovalchuk, Olga
dc.description.abstract: Irradiated cells can signal damage and distress to both close and distant neighbors that have not been directly exposed to the radiation (naïve bystanders). While studies have shown that such bystander effects occur in the shielded brain of animals upon body irradiation, their mechanism remains unexplored. Observed effects may be caused by some blood-borne factors; however they may also be explained, at least in part, by very small direct doses received by the brain that result from scatter or leakage. In order to establish the roles of low doses of scatter irradiation in the brain response, we developed a new model for scatter irradiation analysis whereby one rat was irradiated directly at the liver and the second rat was placed adjacent to the first and received a scatter dose to its body and brain. This work focuses specifically on the response of the latter rat brain to the low scatter irradiation dose. Here, we provide the first experimental evidence that very low, clinically relevant doses of scatter irradiation alter gene expression, induce changes in dendritic morphology, and lead to behavioral deficits in exposed animals. The results showed that exposure to radiation doses as low as 0.115 cGy caused changes in gene expression and reduced spine density, dendritic complexity, and dendritic length in the prefrontal cortex tissues of females, but not males. In the hippocampus, radiation altered neuroanatomical organization in males, but not in females. Moreover, low dose radiation caused behavioral deficits in the exposed animals. This is the first study to show that low dose scatter irradiation influences the brain and behavior in a sex-specific way.
dc.description: Sherpa Romeo green journal: open access
2016-01-01T00:00:00ZFactors influencing cerebral plasticity in the normal and injured brainKolb, BryanTeskey, G. CampbellGibb, Robbin L.https://hdl.handle.net/10133/47262016-11-23T06:04:40Z2010-01-01T00:00:00Zdc.title: Factors influencing cerebral plasticity in the normal and injured brain
dc.contributor.author: Kolb, Bryan; Teskey, G. Campbell; Gibb, Robbin L.
dc.description.abstract: An important development in behavioral neuroscience in the past 20 years has been the
demonstration that it is possible to stimulate functional recovery after cerebral injury in
laboratory animals. Rodent models of cerebral injury provide an important tool for developing
such rehabilitation programs. The models include analysis at different levels including detailed
behavioral paradigms, electrophysiology, neuronal morphology, protein chemistry, and
epigenetics. A significant challenge for the next 20 years will be the translation of this work to
improve the outcome from brain injury and disease in humans. Our goal in the article will be to
synthesize the multidisciplinary laboratory work on brain plasticity and behavior in the injured
brain to inform the development of rehabilitation programs.
dc.description: Sherpa Romeo green journal: open access
2010-01-01T00:00:00ZOlanzapine treatment of adolescent rats causes enduring specific memory impairments and alters cortical development and functionMilstein, Jean A.Elnabawi, AhmedVinish, MonikaSwanson, ThomasEnos, Jennifer K.Bailey, Aileen M.Kolb, BryanFrost, Douglas O.https://hdl.handle.net/10133/47252016-11-23T06:04:36Z2013-01-01T00:00:00Zdc.title: Olanzapine treatment of adolescent rats causes enduring specific memory impairments and alters cortical development and function
dc.contributor.author: Milstein, Jean A.; Elnabawi, Ahmed; Vinish, Monika; Swanson, Thomas; Enos, Jennifer K.; Bailey, Aileen M.; Kolb, Bryan; Frost, Douglas O.
dc.description.abstract: Antipsychotic drugs are increasingly used in children and adolescents to treat a variety of psychiatric disorders. However,
little is known about the long-term effects of early life antipsychotic drug treatment. Most antipsychotic drugs are potent
antagonists or partial agonists of dopamine D2 receptors; atypical antipsychotic drugs also antagonize type 2A serotonin
receptors. Dopamine and serotonin regulate many neurodevelopmental processes. Thus, early life antipsychotic drug
treatment can, potentially, perturb these processes, causing long-term behavioral- and neurobiological impairments. Here,
we treated adolescent, male rats with olanzapine on post-natal days 28–49. As adults, they exhibited impaired working
memory, but normal spatial memory, as compared to vehicle-treated control rats. They also showed a deficit in extinction of
fear conditioning. Measures of motor activity and skill, habituation to an open field, and affect were normal. In the orbitaland
medial prefrontal cortices, parietal cortex, nucleus accumbens core and dentate gyrus, adolescent olanzapine treatment
altered the developmental dynamics and mature values of dendritic spine density in a region-specific manner. Measures of
motor activity and skill, habituation to an open field, and affect were normal. In the orbital- and medial prefrontal cortices,
D1 binding was reduced and binding of GABAA receptors with open Cl2 channels was increased. In medial prefrontal cortex,
D2 binding was also increased. The persistence of these changes underscores the importance of improved understanding of
the enduring sequelae of pediatric APD treatment as a basis for weighing the benefits and risks of adolescent antipsychotic
drug therapy, especially prophylactic treatment in high risk, asymptomatic patients. The long-term changes in
neurotransmitter receptor binding and neural circuitry induced by adolescent APD treatment may also cause enduring
changes in behavioral- and neurobiological responses to other therapeutic- or illicit psychotropic drugs
dc.description: Sherpa Romeo green journal: open access
2013-01-01T00:00:00ZImpulsivity and concussion in juvenile rats: examining molecular and structural aspects of the frontostriatal pathwayHehar, HarleenYeates, KeithKolb, BryanEsser, Michael J.Mychasiuk, Richellehttps://hdl.handle.net/10133/47242016-11-22T20:24:27Z2015-01-01T00:00:00Zdc.title: Impulsivity and concussion in juvenile rats: examining molecular and structural aspects of the frontostriatal pathway
dc.contributor.author: Hehar, Harleen; Yeates, Keith; Kolb, Bryan; Esser, Michael J.; Mychasiuk, Richelle
dc.description.abstract: Impulsivity and poor executive control have been implicated in the pathogenesis of many
developmental and neuropsychiatric disorders. Similarly, concussions/mild traumatic brain
injuries (mTBI) have been associated with increased risk for neuropsychiatric disorders and
the development of impulsivity and inattention. Researchers and epidemiologists have
therefore considered whether or not concussions induce symptoms of attention-deficit/
hyperactivity disorder (ADHD), or merely unmask impulsive tendencies that were already
present. The purpose of this study was to determine if a single concussion in adolescence
could induce ADHD-like impulsivity and impaired response inhibition, and subsequently
determine if inherent impulsivity prior to a pediatric mTBI would exacerbate post-concussion
symptomology with a specific emphasis on impulsive and inattentive behaviours. As these
behaviours are believed to be associated with the frontostriatal circuit involving the nucleus
accumbens (NAc) and the prefrontal cortex (PFC), the expression patterns of 8 genes
(Comt, Drd2, Drd3, Drd4, Maoa, Sert, Tph1, and Tph2) from these two regions were examined.
In addition, Golgi-Cox staining of medium spiny neurons in the NAc provided a neuroanatomical
examination of mTBI-induced structural changes. The study found that a single
early brain injury could induce impulsivity and impairments in response inhibition that were
more pronounced in males. Interestingly, when animals with inherent impulsivity experienced
mTBI, injury-related deficits were exacerbated in female animals. The single concussion
increased dendritic branching, but reduced synaptic density in the NAc, and these
changes were likely associated with the increase in impulsivity. Finally, mTBI-induced
impulsivity was associated with modifications to gene expression that differed dramatically
from the gene expression pattern associated with inherent impulsivity, despite very similar
behavioural phenotypes. Our findings suggest the need to tailor treatment strategies for
mTBI in light of an individual’s premorbid characteristics, given significant differences in
molecular profiles of the frontostriatal circuits that depend upon sex and the etiology of the
behavioural phenotype
dc.description: Sherpa Romeo green journal: open access
2015-01-01T00:00:00ZPrenatal enrichment and recovery from perinatal cortical damage: effects of maternal complex housingGibb, Robbin L.Gonzalez, Claudia L. R.Kolb, Bryanhttps://hdl.handle.net/10133/45972016-09-03T05:04:08Z2014-01-01T00:00:00Zdc.title: Prenatal enrichment and recovery from perinatal cortical damage: effects of maternal complex housing
dc.contributor.author: Gibb, Robbin L.; Gonzalez, Claudia L. R.; Kolb, Bryan
dc.description.abstract: Birth is a particularly vulnerable time for acquiring brain injury. Unfortunately, very few treatments are available for those affected. Here we explore the effectiveness of prenatal intervention in an animal model of early brain damage. We used a complex housing paradigm as a form of prenatal enrichment. Six nulliparous dams and one male rat were placed in complex housing (condomom group) for 12 h per day until the dams’ delivered their pups. At parturition the dams were left in their home (standard) cages with their pups. Four dams were housed in standard cages (cagemom group) throughout pregnancy and with their pups until weaning. At postnatal day 3 (P3) infants of both groups received frontal cortex removals or sham surgery. Behavioral testing began on P60 and included the Morris water task and a skilled reaching task. Brains were processed for Golgi analyses. Complex housing of the mother had a significant effect on the behavior of their pups. Control animals from condomom group outperformed those of the cagemom group in the water task. Condomom animals with lesions performed better than their cagemom cohorts in both the water task and in skilled reaching. Codomom animals showed an increase in cortical thickness at anterior planes and thalamic area at both anterior and posterior regions. Golgi analyses revealed an increase in spine density. These results suggest that prenatal enrichment alters brain organization in manner that is prophylactic for perinatal brain injury. This result could have significant implications for the prenatal management of infants expected to be at risk for difficult birth.
dc.description: Open access journal
2014-01-01T00:00:00ZHarnessing the power of neuroplasticity for interventionKolb, BryanMuhammad, Arifhttps://hdl.handle.net/10133/45782016-08-16T05:04:51Z2014-01-01T00:00:00Zdc.title: Harnessing the power of neuroplasticity for intervention
dc.contributor.author: Kolb, Bryan; Muhammad, Arif
dc.description.abstract: A fundamental property of the brain is its capacity to change with a wide variety of experiences, including injury. Although there are spontaneous reparative changes following injury, these changes are rarely sufficient to support significant functional recovery. Research on the basic principles of brain plasticity is leading to new approaches to treating the injured brain. We review factors that affect synaptic organization in the normal brain, evidence of spontaneous neuroplasticity after injury, and the evidence that factors including postinjury experience, pharmacotherapy, and cell-based therapies, can form the basis of rehabilitation strategies after brain injuries early in life and adulthood.
dc.description: Sherpa Romeo green journal, open access
2014-01-01T00:00:00ZPlasticity in the prefrontal cortex of adult ratsKolb, BryanGibb, Robbin L.https://hdl.handle.net/10133/45772016-09-02T21:21:45Z2015-01-01T00:00:00Zdc.title: Plasticity in the prefrontal cortex of adult rats
dc.contributor.author: Kolb, Bryan; Gibb, Robbin L.
dc.description.abstract: We review the plastic changes of the prefrontal cortex of the rat in response to a
wide range of experiences including sensory and motor experience, gonadal hormones,
psychoactive drugs, learning tasks, stress, social experience, metaplastic experiences, and
brain injury. Our focus is on synaptic changes (dendritic morphology and spine density) in
pyramidal neurons and the relationship to behavioral changes. The most general conclusion
we can reach is that the prefrontal cortex is extremely plastic and that the medial and
orbital prefrontal regions frequently respond very differently to the same experience in the
same brain and the rules that govern prefrontal plasticity appear to differ for those of other
cortical regions.
dc.description: Sherpa Romeo green journal, open access
2015-01-01T00:00:00Z