The Effect of Ionizing Radiation on Cognitive Functions in Mouse Models of Alzheimer's Disease.

The present study demonstrates the effect of combined ionizing radiation (γ rays, 0.24 Gy, 661.7 keV, whole body and 12C, 0.18 Gy, 450 MeV, head region) on the behavior of animals in mouse transgenic models of Alzheimer's disease. Significant improvement of spatial learning and stimulation of locomotor and exploratory behavior were observed in wild-type mice after irradiation. However, an anxiolytic effect and stimulation of locomotor and exploratory behavior were revealed in irradiated mice with tauopathy. Mice with cerebral amyloidosis also exhibited improved learning in the odor recognition test. No negative effects of irradiation were detected.

A Novel Function of the Lysophosphatidic Acid Receptor 3 (LPAR3) Gene in Zebrafish on Modulating Anxiety, Circadian Rhythm Locomotor Activity, and Short-Term Memory.

Lysophosphatidic acid (LPA) is a small lysophospholipid molecule that activates multiple cellular functions through pathways with G-protein-coupled receptors. So far, six LPA receptors (LPAR1 to LPAR6) have been discovered and each one of them can connect to the downstream cell message-transmitting network. A previous study demonstrated that LPA receptors found in blood-producing stem cells can enhance erythropoietic processes through the activation of LPAR3. In the current study, newly discovered functions of LPAR3 were identified through extensive behavioral tests in lpar3 knockout (KO) zebrafish. It was found that the adult lpar3 KO zebrafish display an abnormal movement orientation and altered exploratory behavior compared to that of the control group in the three-dimensional locomotor and novel tank tests, respectively. Furthermore, consistent with those results, in the circadian rhythm locomotor activity test, the lpar3 KO zebrafish showed a lower level of angular velocity and average speed during the light cycles, indicating an hyperactivity-like behavior. In addition, the mutant fish also exhibited considerably higher locomotor activity during the dark cycle. Supporting those findings, this phenomenon was also displayed in the lpar3 KO zebrafish larvae. Furthermore, several important behavior alterations were also observed in the adult lpar3 KO fish, including a lower degree of aggression, less interest in conspecific social interaction, and looser shoal formation. However, there was no significant difference regarding the predator avoidance behavior between the mutant and the control fish. In addition, lpar3 KO zebrafish displayed memory deficiency in the passive avoidance test. These in vivo results support for the first time that the lpar3 gene plays a novel role in modulating behaviors of anxiety, aggression, social interaction, circadian rhythm locomotor activity, and memory retention in zebrafish.

Antidepressant-Like Effect of Low-Intensity Transcranial Ultrasound Stimulation.

OBJECTIVE: Transcranial ultrasound stimulation (TUS) is a noninvasive neuromodulation technique with good spatial resolution and deep penetration. This study aims to investigate whether TUS has antidepressant-like effect to depressed rats. METHODS: Rats were divided into five groups, including two groups (ST-Ctr and ST-Res) for evaluating the short-term impact of restraint stress and three groups (LT-Ctr-ShamTUS, LT-Res-ShamTUS and LT-Res-TUS) for studying the long-term effects of restraint and TUS stimulation. The TUS-treated rats were subjected to 15 min TUS stimulation to the prelimbic cortex every day for 2 weeks after the restraint. Then, depressive symptoms related behavioral outcomes were estimated in ST-Ctr and ST-Res groups (1 week after restraint), as well as in the other three groups (3 weeks after restraint). RESULTS: The 48-h-restraint stress could lead to long lasting reduction of exploratory behavior (1 and 3 weeks after restraint) and protracted anhedonia (only observed 3 weeks after restraint). TUS application successfully reversed the core depressive phenotype, anhedonia, indicated by significantly higher sucrose preference index in LT-Res-TUS group [Formula: see text] than LT-Res-ShamTUS group [Formula: see text]. Furthermore, the brain derived neurotrophic factor expression in left hippocampus was significantly promoted in LT-Res-TUS group [Formula: see text] compared to LT-Res-ShamTUS group [Formula: see text]. In addition, the histologic results of hematoxylin and eosin staining showed no TUS-induced brain tissue injury. CONCLUSION: These results demonstrated that low intensity TUS had antidepressant-like effect. SIGNIFICANCE: TUS has been speculated to have therapeutic effect in depression. This study provide evidence for the antidepressant-like effects of TUS in rats for the first time.

Do arthropods feel anxious during molts?

The molting process of arthropods, chiefly controlled by ecdysteroids, is generally considered very stressful. Our previous investigations have shown that crayfish, after having experienced stressful situations, display anxiety-like behavior (ALB), characterized by aversion to light in a dark/light plus-maze (DLPM). In the present experiments, the spontaneous exploratory behavior of isolated crayfish was analyzed in a DLPM at different stages of their molt cycle. All tested animals displayed transitory aversion to light similar to ALB, before and, mostly, after molting, but not during inter-molt. Injection of ecdysteroids into inter-molt animals elicited ALB after a delay of 4 days, suggesting a long-term, possibly indirect, hormonal effect. Importantly, ecdysteroid-induced ALB was suppressed by the injection of an anxiolytic benzodiazepine. Thus, molts and their hormonal control impose internal stress on crayfish, leading to aversion behavior that has the main characteristics of anxiety. These observations are possibly generalizable to many other arthropods.

Alterations in synaptic density and myelination in response to exposure to high-energy charged particles.

High-energy charged particles are considered particularly hazardous components of the space radiation environment. Such particles include fully ionized energetic nuclei of helium, silicon, and oxygen, among others. Exposure to charged particles causes reactive oxygen species production, which has been shown to result in neuronal dysfunction and myelin degeneration. Here we demonstrate that mice exposed to high-energy charged particles exhibited alterations in dendritic spine density in the hippocampus, with a significant decrease of thin spines in mice exposed to helium, oxygen, and silicon, compared to sham-irradiated controls. Electron microscopy confirmed these findings and revealed a significant decrease in overall synapse density and in nonperforated synapse density, with helium and silicon exhibiting more detrimental effects than oxygen. Degeneration of myelin was also evident in exposed mice with significant changes in the percentage of myelinated axons and g-ratios. Our data demonstrate that exposure to all types of high-energy charged particles have a detrimental effect, with helium and silicon having more synaptotoxic effects than oxygen. These results have important implications for the integrity of the central nervous system and the cognitive health of astronauts after prolonged periods of space exploration.

Physical activity as an option to reduce adverse effect of EMF exposure during pregnancy.

The popularity of using wireless fidelity over the last decades increased apprehensions about impact of high frequency electromagnetic fields (EMF) on health. Most of previous studies mentioned adverse effect of EMF on cognitive processes, but so far, no study has provided a way to control adverse effects of EMF exposure. The purpose of this study was to examine the effect of Wi-Fi EMF and physical activity on spatial learning and motor function in pregnant rat's offspring. Forty Albino-Wistar pregnant rats divided randomly into four groups (EMF, physical activity, combined 2.4GHZ EMF and physical activity and control groups). For assessing spatial learning in 56 post-natal days' old (PND) male offspring, Morris Water Maze (MWM) was used and to examine motor function Open-field test was taken. Although results of MWM test revealed that Wi-Fi modem EMF caused impairment in spatial learning in rats exposed to EMF but physical activity could reduce negative effect of EMF in pregnant rat's offspring who exposed during pregnancy but performed swimming. In addition, results of open-field test showed that litter's motor function in EMF group significantly declined in comparison with physical activity and combined 2.4GHZ EMF and physical activity groups. According to our findings, it can be concluded that execution physical activity individually or along with wave-exposed pregnancy can significantly progressive effect on offspring' cognitive and motor functions.

Persistent nature of alterations in cognition and neuronal circuit excitability after exposure to simulated cosmic radiation in mice.

Of the many perils associated with deep space travel to Mars, neurocognitive complications associated with cosmic radiation exposure are of particular concern. Despite these realizations, whether and how realistic doses of cosmic radiation cause cognitive deficits and neuronal circuitry alterations several months after exposure remains unclear. In addition, even less is known about the temporal progression of cosmic radiation-induced changes transpiring over the duration of a time period commensurate with a flight to Mars. Here we show that rodents exposed to the second most prevalent radiation type in space (i.e. helium ions) at low, realistic doses, exhibit significant hippocampal and cortical based cognitive decrements lasting 1 year after exposure. Cosmic-radiation-induced impairments in spatial, episodic and recognition memory were temporally coincident with deficits in cognitive flexibility and reduced rates of fear extinction, elevated anxiety and depression like behavior. At the circuit level, irradiation caused significant changes in the intrinsic properties (resting membrane potential, input resistance) of principal cells in the perirhinal cortex, a region of the brain implicated by our cognitive studies. Irradiation also resulted in persistent decreases in the frequency and amplitude of the spontaneous excitatory postsynaptic currents in principal cells of the perirhinal cortex, as well as a reduction in the functional connectivity between the CA1 of the hippocampus and the perirhinal cortex. Finally, increased numbers of activated microglia revealed significant elevations in neuroinflammation in the perirhinal cortex, in agreement with the persistent nature of the perturbations in key neuronal networks after cosmic radiation exposure. These data provide new insights into cosmic radiation exposure, and reveal that even sparsely ionizing particles can disrupt the neural circuitry of the brain to compromise cognitive function over surprisingly protracted post-irradiation intervals.

Behavioral Effects of Focal Irradiation in a Juvenile Murine Model.

Chemotherapy has been successfully used to reduce radiation dose and volume for most pediatric patients. However, because of the failure of chemotherapeutic agents to cross the blood-brain barrier and the lack of response of some brain tumors to these agents, radiation therapy is still used to treat many childhood cancers with CNS involvement. In this study, we investigated the radiation effects on cognition and dendritic structure in the hippocampus in juvenile male mice. Twenty-one-day-old male C57BL/6 mice were irradiated using the small animal radiation research platform (SARRP). Animals were exposed to either a 10 Gy single dose or 10 Gy × 2 fractionated doses of X-ray cranial radiation. Five weeks after irradiation, animals were tested for hippocampus-dependent cognitive performance in the Morris water maze. Significant impairment in spatial memory retention was observed in the probe trial after the first day of hidden-platform training (first probe trial) in animals that received either 10 Gy single-dose or 10 Gy × 2 fractionated doses. However, by day 5, mice that received a 10 Gy single dose showed spatial memory retention in the probe trials, whereas mice that received the 20 Gy fractionated doses remained impaired. During Y-maze testing, animals exposed to radiation were impaired; the irradiated mice were not able to distinguish among the three Y-maze arms and spent approximately the same amount of time in all three arms during the retention trial. Radiation significantly compromised the dendritic architecture and reduced spine density throughout the hippocampal trisynaptic network.

Alteration of adaptive behaviors of progeny after maternal mobile phone exposure.

Exposure of pregnant women to radiofrequency (RF) devices raises questions on their possible health consequences for their progeny. We examined the hazard threshold of gestational RF on the progeny's glial homeostasis, sensory-motor gating, emotionality, and novelty seeking and tested whether maternal immune activation would increase RF toxicity. Pregnant dams were daily restrained with loop antennas adjoining the abdomen (fetus body specific absorption rates (SAR): 0, 0.7, or 2.6 W/kg) and received three lipopolysaccharide (LPS) intra-peritoneal injections (0 or 80 µg/kg). Scores in the prepulse startle inhibition, fear conditioning, open field, and elevated plus maze were assessed at adolescence and adulthood. Glial fibrillary acidic protein (GFAP) and interleukines-1ß (ILs) were quantified. LPS induced a SAR-dependent reduction of the prepulse startle inhibition in adults. Activity in the open field was reduced at 2.6 W/kg at adolescence. GFAP and ILs, emotional memory, and anxiety-related behaviors were not modified. These data support the hypothesis that maternal immune activation increased the developmental RF exposure-induced long-term neurobiological impairments. These data support the fact that fetuses who receive combined environmental exposures with RF need special attention for protection.

Awakenings in rats by ultrasounds: A new animal model for paradoxical kinesia.

Paradoxical kinesia refers to a sudden transient ability of akinetic patients to perform motor tasks they are otherwise unable to perform. The mechanisms underlying this phenomenon are unknown due a paucity of valid animal models that faithfully reproduce paradoxical kinesia. Here, in a first experiment, we present a new method to study paradoxical kinesia by "awakening" cataleptic rats through presenting appetitive 50-kHz ultrasonic vocalizations (USV), which are typical for social situations with positive valence, like juvenile play or sexual encounters ("rat laughter"). Rats received systemic haloperidol to induce catalepsy, which was assessed by means of the bar test. During that test, 50-kHz USV, time- and amplitude-matched white noise (NOISE), or background noise (BACKGROUND) were played back and compared to SILENCE. Every animal was exposed to all four acoustic stimuli in random order, with four independent groups of rats being tested. Only when exposed to playback of appetitive 50-kHz USV, the otherwise akinetic rats rapidly started to move efficiently. The acoustic control stimuli, in contrast, did not release rats from catalepsy, despite eliciting the auditory pinna reflex and head movements towards the sound source. Moreover, in a second experiment, playback of aversive 22-kHz USV and relevant acoustic control stimuli did also not significantly affect catalepsy time. Together, our animal model provides a completely new approach to study mechanisms of paradoxical kinesia, which might help to improve behavioral therapies for Parkinson's disease and other disorders, where akinetic or cataleptic states occur.

Cerebral impact of prenatal irradiation by 131I: an experimental model of clinical neuroradioembryological effects. / VPLYV PRENATAL'NOGO OPROMINENNIa 131I NA GOLOVNYY̆ MOZOK: EKSPERYMENTAL'NA MODEL' KLINIChNYKh NEY̆RORADIOEMBRIOLOGIChNYKh EFEKTIV.

Human brain in prenatal period is a most vulnerable to ionizing radiation body structure. Unlike atomic bombings or radiological interventions in healthcare leading at most to external irradiation the intensive internal exposure may occur upon nuclear reactor accidents followed by substantial release and fallout of radioactive 131I. The latter can lead to specific neuroradioembryological effects. OBJECTIVE: To create an experimental model of prenatal cerebral radiation effects of 131I in human and to determine the experimental and clinical neuroradioembryological effects.Study object. The neuroradioembryological effects in Vistar rats exposed to 131I in prenatal period. Nervous system status and mental status in 104 persons exposed to ionizing radiation in utero due to the ChNPP accident and the same in 78 not exposed subjects. METHODS: Experimental i.e. behavioral techniques, including the spontaneous locomotive, exploratory activity and learning ability assessment, clinical i.e. neuropsychiatric, neuro and psychometric, neuropsychological, neurophys iological methods, both with dosimetric and statistical methods were applied. RESULTS: Intrauterine irradiation of Wistar rats by 131I was simulated on a model of one time oral 27.5 kBq radionu clide administration in the mid gestation period (0.72±0.14 Gy fetal thyroid dose), which provides extrapolation of neuroradioembryological effects in rats to that in humans exposed to intrauterine radiation as a result of the Chornobyl catastrophe. Abnormalities in behavioral reactions and decreased output of conditioned reflex reactions identified in the 10 month old rats suggest a deterioration of cerebral cognition in exposed animals. Specific cog nitive deficit featuring a disharmonic intellectual development through the relatively decreased verbal intelligence versus relative increase of nonverbal one is remained in prenatally exposed persons. This can indicate to dysfunc tion of cortical limbic system with especial involvement of a dominant hemisphere hippocampus. Decreased theta band spectral power (4-7 Hz range) of cerebral bioelectrical activity in the left frontotemporal area is suggestive of hippocampal dysfunction mainly in dominant hemisphere of prenatally irradiated persons. Disorders of hippocam pal neurogenesis due to prenatal exposure by radioactive iodine can be a biologic basis here. Innovative approach es in social adaptation, psychoprophylaxis and psychorehabilitation involve the maximum effective application and development of just the most developed psychological and cognitive abilities in survivors.

Long-Term Deficits in Behavior Performances Caused by Low- and High-Linear Energy Transfer Radiation.

Efforts to protect astronauts from harmful galactic cosmic radiation (GCR) require a better understanding of the effects of GCR on human health. In particular, little is known about the lasting effects of GCR on the central nervous system (CNS), which may lead to behavior performance deficits. Previous studies have shown that high-linear energy transfer (LET) radiation in rodents leads to short-term declines in a variety of behavior tests. However, the lasting impact of low-, medium- and high-LET radiation on behavior are not fully defined. Therefore, in this study C57BL/6 male mice were irradiated with 100 or 250 cGy of γ rays (LET ∼0.3 KeV/µm), 10 or 100 cGy of 1H at 1,000 MeV/n (LET ∼0.2 KeV/µm), 28Si at 300 MeV/n (LET ∼69 KeV/µm) or 56Fe at 600 MeV/n (LET of ∼180 KeV/µm), and behavior metrics were collected at 5 and 9 months postirradiation to analyze differences among radiation qualities and doses. A significant dose effect was observed on recognition memory and activity levels measured 9 months postirradiation, regardless of radiation source. In contrast, we observed that each ion species had a distinct effect on anxiety, motor coordination and spatial memory at extended time points. Although 28Si and 56Fe are both regarded as high-LET particles, they were shown to have different detrimental effects on behavior. In summary, our findings suggest that GCR not only affects the CNS in the short term, but also has lasting damaging effects on the CNS that can cause sustained declines in behavior performance.

Egocentric and allocentric representations in auditory cortex.

A key function of the brain is to provide a stable representation of an object's location in the world. In hearing, sound azimuth and elevation are encoded by neurons throughout the auditory system, and auditory cortex is necessary for sound localization. However, the coordinate frame in which neurons represent sound space remains undefined: classical spatial receptive fields in head-fixed subjects can be explained either by sensitivity to sound source location relative to the head (egocentric) or relative to the world (allocentric encoding). This coordinate frame ambiguity can be resolved by studying freely moving subjects; here we recorded spatial receptive fields in the auditory cortex of freely moving ferrets. We found that most spatially tuned neurons represented sound source location relative to the head across changes in head position and direction. In addition, we also recorded a small number of neurons in which sound location was represented in a world-centered coordinate frame. We used measurements of spatial tuning across changes in head position and direction to explore the influence of sound source distance and speed of head movement on auditory cortical activity and spatial tuning. Modulation depth of spatial tuning increased with distance for egocentric but not allocentric units, whereas, for both populations, modulation was stronger at faster movement speeds. Our findings suggest that early auditory cortex primarily represents sound source location relative to ourselves but that a minority of cells can represent sound location in the world independent of our own position.

Later Life Changes in Hippocampal Neurogenesis and Behavioral Functions After Low-Dose Prenatal Irradiation at Early Organogenesis Stage.

PURPOSE: To investigate long-term changes in behavioral functions of mice after exposure to low-dose prenatal radiation at an early organogenesis stage. METHODS AND MATERIALS: Pregnant C57BL/6J mice were irradiated (20 cGy) at postcoitus day 5.5. The male and female offspring were subjected to different behavioral assays for affective, motor, and cognitive functions at 3, 6, and 12 months of age. Behavioral functions were further correlated with the population of CA1 and CA3 pyramidal neurons and immature neurons in hippocampal dentate gyrus. RESULTS: Prenatally exposed mice of different age groups showed a sex-specific pattern of sustained changes in behavioral functions. Male mice showed significant changes in anxiety-like phenotypes, learning, and long-term memory at age 3 months. At 6 months of age such behavioral functions were recovered to a normal level but could not be sustained at age 12 months. Female mice showed an appreciable recovery in almost all behavioral functions at 12 months. Patterns of change in learning and long-term memory were comparable to the population of CA1 and CA3 pyramidal neurons and doublecortin-positive neurons in hippocampus. CONCLUSION: Our finding suggests that prenatal (early organogenesis stage) irradiation even at a lower dose level (20 cGy) is sufficient to cause potential changes in neurobehavioral function at later stages of life. Male mice showed relatively higher vulnerability to radiation-induced neurobehavioral changes as compared with female.

Combined effects of antiorthostatic suspension and ionizing radiation on the behaviour and neurotransmitters changes in different brain structures of rats.

Space flight factors (SFF) significantly affect the operating activity of astronauts during deep space missions. In contrast to an orbital flight, leaving the Earth's magnetic field is fraught with the dangers of exposure to ionizing radiation and more specifically, the high-energy nuclei component of galactic cosmic rays. Microgravity, just another critical non-radiation factor, significantly affects the normal functioning of the CNS. Some morphological structures of the brain, such as the prefrontal cortex and the hippocampus, that are rich in monoaminergic and acetylcholinergic neurones, are the most sensitive to the effects of ionizing radiation and non-radiation spaceflight factors (SFF). In this work we have studied the combined effects of microgravity (in antiorthostatic suspension model, AS) and irradiation (γ-ray and protons in spread-out Bragg peak) on the behaviour, cognitive abilities, and metabolism of monoamines and acetylcholine in the key structures of the rat's brain. Irradiation (as independently as combined with AS) resulted in the decrease of thigmotaxis in rats. Learning problems, caused by the malfunctioning of the working memory but not the spatial memory, were observed in response to AS as well as to the SFF in combination. Analysis of monoamines metabolism showed that the serotoninergic system was the most affected by the SFF. Concentration of acetylcholine in the hippocampus significantly increased in the groups of irradiated rats, and in the groups which were exposed to the SFF in combination, compared to the rats exposed only to AS.

Optogenetically Blocking Sharp Wave Ripple Events in Sleep Does Not Interfere with the Formation of Stable Spatial Representation in the CA1 Area of the Hippocampus.

During hippocampal sharp wave/ripple (SWR) events, previously occurring, sensory input-driven neuronal firing patterns are replayed. Such replay is thought to be important for plasticity-related processes and consolidation of memory traces. It has previously been shown that the electrical stimulation-induced disruption of SWR events interferes with learning in rodents in different experimental paradigms. On the other hand, the cognitive map theory posits that the plastic changes of the firing of hippocampal place cells constitute the electrophysiological counterpart of the spatial learning, observable at the behavioral level. Therefore, we tested whether intact SWR events occurring during the sleep/rest session after the first exploration of a novel environment are needed for the stabilization of the CA1 code, which process requires plasticity. We found that the newly-formed representation in the CA1 has the same level of stability with optogenetic SWR blockade as with a control manipulation that delivered the same amount of light into the brain. Therefore our results suggest that at least in the case of passive exploratory behavior, SWR-related plasticity is dispensable for the stability of CA1 ensembles.

Long-term outcome of changes in cognitive function of young rats after various/different doses of whole brain irradiation.

OBJECTIVE: To characterize the early delayed and late-delayed cognitive dysfunction induced by various doses of whole brain irradiation in young rats. METHODS: One-month-old Sprague-Dawley male rats were divided randomly into the 0 (control), 0 (anesthesia control), 2, 10, 20, and 30-Gy groups. Each group was then subdivided into 4 groups according to the experimental intervals: 1, 2, 3, and 6 months after radiation. Rats were irradiated using a 4-MeV electron beam, which was generated by a linear accelerator. Sequential behavioral tests, including open field, novel location and novel object recognition and Morris water maze were performed after radiation. Changes in gross neurological symptoms, body weight, topical skin response, and histopathology were observed. RESULTS: In the open field test, there were no radiation-induced alterations found. In the novel location and novel object recognition tests, rats of the 20-Gy group spent less time exploring the novel object and novel location 3 months after irradiation. During the place navigation test, the spatial working memory of the 30 and 20-Gy irradiated rats were impaired from 1 to 2 months after irradiation, respectively. In the spatial probe test, the 20 and 30-Gy irradiated rats spent less time in the critical region compared to control rats at 3 and 6 months post-irradiation. Morphological changes, including edema, vascular dilation, focal necrosis, demyelination, and adjacent reactive gliosis were observed in the 30-Gy irradiation group. CONCLUSION: More than 20 Gy of whole brain irradiation dose can cause significant cognitive dysfunction in young rats.

Neonatal exposure to whole body ionizing radiation induces adult neurobehavioural defects: Critical period, dose--response effects and strain and sex comparison.

Development of the brain includes periods which can be critical for its normal maturation. The present study investigates specifically vulnerable peri-/postnatal periods in mice which are essential for understanding the etiology behind radiation induced neurotoxicity and functional defects, including evaluation of neurotoxicity between sexes or commonly used laboratory mouse strains following low/moderate doses of ionizing radiation (IR). Male Naval Medical Research Institute (NMRI) mice, whole body irradiated to a single 500 mGy IR dose, on postnatal day (PND) 3 or PND 10 showed an altered adult spontaneous behaviour and impaired habituation capacity, whereas irradiation on PND 19 did not have any impact on the studied variables. Both NMRI and C57bl/6 male and female mice showed an altered adult spontaneous behaviour and impaired habituation following a single whole body irradiation of 500 or 1000 mGy, but not after 20 or 100 mGy, on PND 10. The present study shows that exposure to low/moderate doses of IR during critical life stages might be involved in the induction of neurological/neurodegenerative disorder/disease. A specifically vulnerable period for radiation induced neurotoxicity seems to be around PND 3-10 in mice. Further studies are needed to investigate mechanisms involved in induction of developmental neurotoxicity following low-dose irradiation.

Effect of behavioral testing on spine density of basal dendrites in the CA1 region of the hippocampus modulated by (56)Fe irradiation.

A unique feature of the space radiation environment is the presence of high-energy charged particles, including (56)Fe ions, which can present a significant hazard to space flight crews during and following a mission. (56)Fe irradiation-induced cognitive changes often involve alterations in hippocampal function. These alterations might involve changes in spine morphology and density. In addition to irradiation, performing a cognitive task can also affect spine morphology. Therefore, it is often hard to determine whether changes in spine morphology and density are due to an environmental challenge or group differences in performance on cognitive tests. In this study, we tested the hypothesis that the ability of exploratory behavior to increase specific measures of hippocampal spine morphology and density is affected by (56)Fe irradiation. In sham-irradiated mice, exploratory behavior increased basal spine density in the CA1 region of the hippocampus and the enclosed blade of the dentate gyrus. These effects were not seen in irradiated mice. In addition, following exploratory behavior, there was a trend toward a decrease in the percent stubby spines on apical dendrites in the CA3 region of the hippocampus in (56)Fe-irradiated, but not sham-irradiated, mice. Other hippocampal regions and spine measures affected by (56)Fe irradiation showed comparable radiation effects in behaviorally naïve and cognitively tested mice. Thus, the ability of exploratory behavior to alter spine density and morphology in specific hippocampal regions is affected by (56)Fe irradiation.

Acute food deprivation enhances fear extinction but inhibits long-term depression in the lateral amygdala via ghrelin signaling.

Fear memory-encoding thalamic input synapses to the lateral amygdala (T-LA) exhibit dynamic efficacy changes that are tightly correlated with fear memory strength. Previous studies have shown that auditory fear conditioning involves strengthening of synaptic strength, and conversely, fear extinction training leads to T-LA synaptic weakening and occlusion of long-term depression (LTD) induction. These findings suggest that the mechanisms governing LTD at T-LA synapses may determine the behavioral outcomes of extinction training. Here, we explored this hypothesis by implementing food deprivation (FD) stress in mice to determine its effects on fear extinction and LTD induction at T-LA synapses. We found that FD increased plasma acylated ghrelin levels and enhanced fear extinction and its retention. Augmentation of fear extinction by FD was blocked by pretreatment with growth hormone secretagogue receptor type-1a antagonist D-Lys(3)-GHRP-6, suggesting an involvement of ghrelin signaling. Confirming previous findings, two distinct forms of LTD coexist at thalamic inputs to LA pyramidal neurons that can be induced by low-frequency stimulation (LFS) or paired-pulse LFS (PP-LFS) paired with postsynaptic depolarization, respectively. Unexpectedly, we found that FD impaired the induction of PP-LFS- and group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG)-induced LTD, but not LFS-induced LTD. Ghrelin mimicked the effects of FD to impair the induction of PP-LFS- and DHPG-induced LTD at T-LA synapses, which were blocked by co-application of D-Lys(3)-GHRP-6. The sensitivity of synaptic transmission to 1-naphthyl acetyl spermine was not altered by either FD or ghrelin treatment. These results highlight distinct features of fear extinction and LTD at T-LA synapses.