Radiation-induced cognitive impairment and altered diffusion tensor imaging in a juvenile rat model of cranial radiotherapy.

Purpose: To assess the long-term effects of fractionated whole brain irradiation (fWBI) using diffusion tensor imaging (DTI) and behavior in a pediatric rodent model for the clinical presentation of adult pediatric cancer survivors.

Materials And Methods: Five-week-old, male F344xBN rats were randomized to receive 0, 5, or 6.5 Gy fractions biweekly for 3 weeks, resulting in Sham, Irradiated-30 (IR-30) and IR-39 Gy total dose groups.

Growth hormone and insulin-like growth factor-I alter hippocampal excitatory synaptic transmission in young and old rats.

In rats, as in humans, normal aging is characterized by a decline in hippocampal-dependent learning and memory, as well as in glutamatergic function. Both growth hormone (GH) and insulin-like growth factor-I (IGF-I) levels have been reported to decrease with age, and treatment with either GH or IGF-I can ameliorate age-related cognitive decline. Interestingly, acute GH and IGF-I treatments enhance glutamatergic synaptic transmission in the rat hippocampus of juvenile animals.

Imaging radiation-induced normal tissue injury.

Technological developments in radiation therapy and other cancer therapies have led to a progressive increase in five-year survival rates over the last few decades. Although acute effects have been largely minimized by both technical advances and medical interventions, late effects remain a concern. Indeed, the need to identify those individuals who will develop radiation-induced late effects, and to develop interventions to prevent or ameliorate these late effects is a critical area of radiobiology research.

Growth hormone modulates hippocampal excitatory synaptic transmission and plasticity in old rats.

Alterations in the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPA-R) and N-methyl-D-aspartate receptor (NMDA-R) have been documented in aged animals and may contribute to changes in hippocampal-dependent memory. Growth hormone (GH) regulates AMPA-R and NMDA-R-dependent excitatory transmission and decreases with age. Chronic GH treatment mitigates age-related cognitive decline.

Aging masks detection of radiation-induced brain injury.

Fractionated partial or whole-brain irradiation (fWBI) is a widely used, effective treatment for primary and metastatic brain tumors, but it also produces radiation-induced brain injury, including cognitive impairment. Radiation-induced neural changes are particularly problematic for elderly brain tumor survivors who also experience age-dependent cognitive impairment. Accordingly, we investigated i] radiation-induced cognitive impairment, and ii] potential biomarkers of radiation-induced brain injury in a rat model of aging.

Age-related synapse loss in hippocampal CA3 is not reversed by caloric restriction.

Caloric restriction (CR) is a reduction of total caloric intake without a decrease in micronutrients or a disproportionate reduction of any one dietary component. While CR attenuates age-related cognitive deficits in tasks of hippocampal-dependent memory, the cellular mechanisms by which CR improves this cognitive decline are poorly understood. Previously, we have reported age-related decreases in key synaptic proteins in the CA3 region of the hippocampus that are stabilized by lifelong CR.

Differential effects of radiation and age on diffusion tensor imaging in rats.

Greater than 50% of adults and approximately 100% of children who survive >6 months after fractionated partial or whole-brain radiotherapy develop cognitive impairments. Noninvasive methods are needed for detecting and tracking the radiation-induced brain injury associated with these impairments. Using magnetic resonance imaging, we sought to detect structural changes associated with brain injury in our rodent model of fractionated whole-brain irradiation (fWBI) induced cognitive impairment and to compare those changes with alterations that occur during the aging process.

Early-onset GH deficiency results in spatial memory impairment in mid-life and is prevented by GH supplementation.

GH levels increase to high concentrations immediately before puberty then progressively decline with age. GH deficiency (GHD) originating in childhood is treated with GH supplementation to foster somatic development during adolescence. It is not clear if or how early GH replacement affects memory in adulthood, or whether it can prevent the cognitive deficits commonly observed in adults with childhood-onset GHD.

Maintenance of white matter integrity in a rat model of radiation-induced cognitive impairment.

Radiation therapy is used widely to treat primary and metastatic brain tumors, but also can lead to delayed neurological complications. Since maintenance of myelin integrity is important for cognitive function, the present study used a rat model that demonstrates spatial learning and memory impairment 12 months following fractionated whole-brain irradiation (WBI) at middle age to investigate WBI-induced myelin changes. In this model, 12-month Fischer 344 x Brown Norway rats received 9 fractions of 5 Gy delivered over 4.

Stability of local brain levels of insulin-like growth factor-I in two well-characterized models of decreased plasma IGF-I.

Insulin-like growth factor-I (IGF-I), a functionally important neurotrophic factor, impacts tissues throughout the body including the central nervous system. In addition to the significant proportion of IGF-I that is synthesized in the liver and released into the plasma, IGF-I is expressed locally in tissues. The present study investigated the relationship between plasma and local brain levels of IGF-I in two well-characterized models of decreased IGF-I.

Hippocampal neuron number is unchanged 1 year after fractionated whole-brain irradiation at middle age.

Purpose: To determine whether hippocampal neurons are lost 12 months after middle-aged rats received a fractionated course of whole-brain irradiation (WBI) that is expected to be biologically equivalent to the regimens used clinically in the treatment of brain tumors.

Methods And Materials: Twelve-month-old Fischer 344 X Brown Norway male rats were divided into WBI and control (CON) groups (n = 6 per group). Anesthetized WBI rats received 45 Gy of (137)Cs gamma rays delivered as 9 5-Gy fractions twice per week for 4.

Bilateral cochlear ablation in postnatal rat disrupts development of banded pattern of projections from the dorsal nucleus of the lateral lemniscus to the inferior colliculus.

Axonal projections from the dorsal nucleus of the lateral lemniscus (DNLL) distribute contralaterally in a pattern of banded layers in the central nucleus of the inferior colliculus (IC). The banded pattern of DNLL projections is already in the IC by onset of hearing in postnatal rat pups. Previously, it was shown that unilateral cochlear ablation in neonatal rat pups disrupted the banded pattern in IC for the projections of the DNLL contralateral to the ablation but not those of the DNLL ipsilateral to the ablation.

Caloric restriction and age affect synaptic proteins in hippocampal CA3 and spatial learning ability.

Caloric restriction (CR) is a daily reduction of total caloric intake without a decrease in micronutrients or disproportionate reduction of any one dietary component. CR can increase lifespan reliably in a wide range of species and appears to counteract some aspects of the aging process throughout the body. The effects on the brain are less clear, but moderate CR seems to attenuate age-related cognitive decline.

Distinct mechanisms of ethanol potentiation of local and paracapsular GABAergic synapses in the rat basolateral amygdala.

Converging lines of behavioral and pharmacological evidence suggest that GABAergic synapses in the basolateral amygdala (BLA) may play an integral role in mediating the anxiolytic effects of ethanol (EtOH). Since anxiety is thought to play an important role in the development of, and relapse to, alcoholism, elucidating the mechanisms through which EtOH modulates GABAergic synaptic transmission in the BLA may be fundamental in understanding the etiology of this disease. A recent study in mice has shown that principal cells within the BLA receive inhibitory input from two distinct types of GABAergic interneurons: a loosely distributed population of local interneurons and a dense network of paracapsular (pcs) GABAergic cells clustered along the external capsule border.

Cochlear ablation in adult ferrets results in changes in insulin-like growth factor-1 and synaptophysin immunostaining in the cochlear nucleus.

Afferent activity modulates synaptic plasticity as well as the levels of activity-dependent molecules such as growth factors. Disruption of this activity due to deafferentation has been shown to result in an altered trophic support and consequently in changes in neuronal excitability and synaptic transmission. In the present study, to test whether lack of cochlear integrity results in changes in insulin-growth factor-1 (IGF-1) and synaptophysin immunostaining in the cochlear nucleus, the first relay structure in the auditory pathway, unilateral cochlear ablations were performed in adult ferrets.

Caloric restriction eliminates the aging-related decline in NMDA and AMPA receptor subunits in the rat hippocampus and induces homeostasis.

Caloric restriction (CR) extends life span and ameliorates the aging-related decline in hippocampal-dependent cognitive function. In the present study, we compared subunit levels of NMDA and AMPA types of the glutamate receptor and quantified total synapses and multiple spine bouton (MSB) synapses in hippocampal CA1 from young (10 months), middle-aged (18 months), and old (29 months) Fischer 344xBrown Norway rats that were ad libitum (AL) fed or caloric restricted (CR) from 4 months of age. Each of these parameters has been reported to be a potential contributor to hippocampal function.

Effects of aging and caloric restriction on dentate gyrus synapses and glutamate receptor subunits.

Caloric restriction (CR) attenuates aging-related degenerative processes throughout the body. It is less clear, however, whether CR has a similar effect in the brain, particularly in the hippocampus, an area important for learning and memory processes that often are compromised in aging. In order to evaluate the effect of CR on synapses across lifespan, we quantified synapses stereologically in the middle molecular layer of the dentate gyrus (DG) of young, middle aged and old Fischer 344 x Brown Norway rats fed ad libitum (AL) or a CR diet from 4 months of age.

Development of banded afferent compartments in the inferior colliculus before onset of hearing in ferrets.

Axonal projections from the lateral superior olivary nuclei (LSO), as well as from the dorsal cochlear nucleus (DCN) and dorsal nucleus of the lateral lemniscus (DNLL), converge in frequency-ordered layers in the central nucleus of the inferior colliculus (IC) where they distribute among different synaptic compartments. A carbocyanine dye, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI), was used as a tracer to study the postnatal development of axonal projections in the ferret IC. The results indicated that projections from all three nuclei are present at birth, but are not segregated into bands.

Synaptophysin and insulin-like growth factor-1 immunostaining in the central nucleus of the inferior colliculus in adult ferrets following unilateral cochlear removal: a densitometric analysis.

In the present study, unilateral cochlear ablations were performed in adult ferrets to evaluate possible time-dependent modifications of synaptophysin and insulin-like growth factor-1 (IGF-1) in the central nucleus of the inferior colliculus (CNIC). Using densitometric analysis, synaptophysin and IGF-1 immunostaining were assessed at 1 (PA1) and 90 (PA90) days after cochlear ablation. The results demonstrated that 1 day after the lesion there was an increase in the levels of synaptophysin immunostaining bilaterally in the CNIC compared to control animals.

Spatial learning and memory deficits after whole-brain irradiation are associated with changes in NMDA receptor subunits in the hippocampus.

Whole-brain irradiation is used for the treatment of brain tumors, but can it also induce neural changes, with progressive dementia occurring in 20-50% of long-term survivors. The present study investigated whether 45 Gy of whole-brain irradiation delivered to 12-month-old Fischer 344 x Brown Norway rats as nine fractions over 4.5 weeks leads to impaired Morris water maze (MWM) performance 12 months later.

Unilateral cochlear ablation before hearing onset disrupts the maintenance of dorsal nucleus of the lateral lemniscus projection patterns in the rat inferior colliculus.

During postnatal development, ascending and descending auditory inputs converge to form fibrodendritic layers within the central nucleus of the inferior colliculus (IC). Before the onset of hearing, specific combinations of inputs segregate into bands separated by interband spaces. These bands may define functional zones within the IC.

Growth hormone and IGF-I modulate local cerebral glucose utilization and ATP levels in a model of adult-onset growth hormone deficiency.

Decreases in plasma IGF-I levels that occur with age have been hypothesized to contribute to the genesis of brain aging. However, support for this hypothesis would be strengthened by evidence that growth hormone (GH)/IGF-I deficiency in young animals produces a phenotype similar to that found in aged animals. As a result, we developed a unique model of adult-onset GH/IGF-I deficiency by using dwarf rats specifically deficient in GH and IGF-I.

Synaptogenesis in the inferior colliculus of the pre-hearing postnatal ferret.

Although intrinsic organization in the inferior colliculus (IC) has been surveyed in a variety of species, current knowledge of synaptogenesis within the mammalian inferior colliculus is limited. The present study surveyed the ultrastructure of the central nucleus of the inferior colliculus in postnatal day (P) P4, P7, P14, and P28 ferrets, prior to the onset of hearing at the end of the first postnatal month with the goal of beginning to characterize the time course of synapse formation in relation to the development of afferent projection patterns within the IC. Results suggest that initial synaptogenesis has occurred in the IC by P4 and continues during the period when maturation of the distribution of axons from brainstem auditory nuclei is taking place.

Maintenance of inhibitory interneurons and boutons in sensorimotor cortex between middle and old age in Fischer 344 X Brown Norway rats.

Ultrastructurally identified inhibitory synapses in layer II of rat sensorimotor cortex decline between middle and old age [Poe, B.H., Linville, C.