New Concerns for Neurocognitive Function during Deep Space Exposures to Chronic, Low Dose-Rate, Neutron Radiation.

As NASA prepares for a mission to Mars, concerns regarding the health risks associated with deep space radiation exposure have emerged. Until now, the impacts of such exposures have only been studied in animals after acute exposures, using dose rates ∼1.5×105 higher than those actually encountered in space. Using a new, low dose-rate neutron irradiation facility, we have uncovered that realistic, low dose-rate exposures produce serious neurocognitive complications associated with impaired neurotransmission. Chronic (6 month) low-dose (18 cGy) and dose rate (1 mGy/d) exposures of mice to a mixed field of neutrons and photons result in diminished hippocampal neuronal excitability and disrupted hippocampal and cortical long-term potentiation. Furthermore, mice displayed severe impairments in learning and memory, and the emergence of distress behaviors. Behavioral analyses showed an alarming increase in risk associated with these realistic simulations, revealing for the first time, some unexpected potential problems associated with deep space travel on all levels of neurological function.

Image-guided cranial irradiation-induced ablation of dentate gyrus neurogenesis impairs extinction of recent morphine reward memories.

Dentate gyrus adult neurogenesis is implicated in the formation of hippocampal-dependent contextual associations. However, the role of adult neurogenesis during reward-based context-dependent paradigms-such as conditioned place preference (CPP)-is understudied. Therefore, we used image-guided, hippocampal-targeted X-ray irradiation (IG-IR) and morphine CPP to explore whether dentate gyrus adult neurogenesis plays a role in reward memories created in adult C57BL/6J male mice. In addition, as adult neurogenesis appears to participate to a greater extent in retrieval and extinction of recent (<48 hr posttraining) versus remote (>1 week posttraining) memories, we specifically examined the role of adult neurogenesis in reward-associated contextual memories probed at recent and remote timepoints. Six weeks post-IG-IR or Sham treatment, mice underwent morphine CPP. Using separate groups, retrieval of recent and remote reward memories was found to be similar between IG-IR and Sham treatments. Interestingly, IG-IR mice showed impaired extinction-or increased persistence-of the morphine-associated reward memory when it was probed 24-hr (recent) but not 3-weeks (remote) postconditioning relative to Sham mice. Taken together, these data show that hippocampal-directed irradiation and the associated decrease in dentate gyrus adult neurogenesis affect the persistence of recently-but not remotely-probed reward memory. These data indicate a novel role for adult neurogenesis in reward-based memories and particularly the extinction rate of these memories. Consideration of this work may lead to better understanding of extinction-based behavioral interventions for psychiatric conditions characterized by dysregulated reward processing.

Optical inactivation of synaptic AMPA receptors erases fear memory.

The synaptic delivery of neurotransmitter receptors, such as GluA1 AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors, mediates important processes in cognitive function, including memory acquisition and retention. Understanding the roles of these receptors has been hampered by the lack of a method to inactivate them in vivo with high spatiotemporal precision. We developed a technique to inactivate synaptic GluA1 AMPA receptors in vivo using chromophore-assisted light inactivation (CALI). We raised a monoclonal antibody specific for the extracellular domain of GluA1 that induced effective CALI when conjugated with a photosensitizer (eosin). Mice that had been injected in the CA1 hippocampal region with the antibody conjugate underwent a fear memory task. Exposing the hippocampus to green light using an implanted cannula erased acquired fear memory in the animals by inactivation of synaptic GluA1. Our optical technique for inactivating synaptic proteins will enable elucidation of their physiological roles in cognition.

Role of extrinsic noise in the sensitivity of the rod pathway: rapid dark adaptation of nocturnal vision in humans.

UNLABELLED: Rod-mediated 500 nm test spots were flashed in Maxwellian view at 5 deg eccentricity, both on steady 10.4 deg fields of intensities (I) from 0.00001 to 1.0 scotopic troland (sc td) and from 0.2 s to 1 s after extinguishing the field. On dim fields, thresholds of tiny (5') tests were proportional to √I (Rose-DeVries law), while thresholds after extinction fell within 0.6 s to the fully dark-adapted absolute threshold. Thresholds of large (1.3 deg) tests were proportional to I (Weber law) and extinction thresholds, to √I. CONCLUSIONS: rod thresholds are elevated by photon-driven noise from dim fields that disappears at field extinction; large spot thresholds are additionally elevated by neural light adaptation proportional to √I. At night, recovery from dimly lit fields is fast, not slow.

Effect of ablated hippocampal neurogenesis on the formation and extinction of contextual fear memory.

Newborn neurons in the subgranular zone (SGZ) of the hippocampus incorporate into the dentate gyrus and mature. Numerous studies have focused on hippocampal neurogenesis because of its importance in learning and memory. However, it is largely unknown whether hippocampal neurogenesis is involved in memory extinction per se. Here, we sought to examine the possibility that hippocampal neurogenesis may play a critical role in the formation and extinction of hippocampus-dependent contextual fear memory. By methylazoxymethanol acetate (MAM) or gamma-ray irradiation, hippocampal neurogenesis was impaired in adult mice. Under our experimental conditions, only a severe impairment of hippocampal neurogenesis inhibited the formation of contextual fear memory. However, the extinction of contextual fear memory was not affected. These results suggest that although adult newborn neurons contribute to contextual fear memory, they may not be involved in the extinction or erasure of hippocampus-dependent contextual fear memory.

Repeated peripheral electrical stimulations suppress both morphine-induced CPP and reinstatement of extinguished CPP in rats: accelerated expression of PPE and PPD mRNA in NAc implicated.

Previous studies have shown that peripheral electrical stimulation (PES) can suppress morphine-induced conditioned place preference (CPP) and the reinstatement of extinguished CPP in the rat. The present study was performed to elucidate if preproenkephalin (PPE) and preprodynorphin (PPD) mRNAs in the nucleus accumbens (NAc) play a role in this event. Rats were trained with morphine for 4 days to establish CPP paradigm. They were then given 15-min test once a day for eight consecutive days for extinction trial. Twenty-four hours after the 8th session of extinction trials, rats were given peripheral electrical stimulation (PES) at 2 or 100 Hz once a day for 3 days, then a morphine-priming injection at a dose of 1, 2, or 4 mg/kg to reinstate the extinguished CPP. At the end of the experiment, PPE and PPD mRNA levels in the nucleus acccumbens (NAc) were determined by the semiquantitative RT-PCR technique. The results showed that PES at 2- and 100-Hz administered 30 min a day for 3 days suppressed both the expression of morphine-induced CPP and the reinstatement of extinguished CPP. PES at 2 Hz increased preproenkephalin (PPE) mRNA levels, whereas PES of 100 Hz that of preprodynorphin (PPD) mRNA levels in the NAc. These findings suggest that enkephalin and dynorphin in NAc may play important roles in the mechanisms underlying the inhibitory effect of PES on the expression and reinstatement of morphine-induced CPP in rats.

The use of alert behaving mice in the study of learning and memory processes.

The availability of transgenic mice that mimic human neurodegenerative processes has made it necessary to develop new recording and stimulating techniques capable of being applied in this species. We have studied here the motor learning and memory capabilities of wild-type and transgenic mice with deficits in cognitive functions, using classical conditioning procedures. We have developed an electrical shock/SHOCK paradigm corresponding to a trace classical conditioning; that is, a learning task involving the cerebral cortex, including the hippocampus. The conditioning procedure is a modification of the air-puff/AIR-PUFF conditioning (Gruart et al., J. Neurophysiol. 74:226, 1995). Animals were implanted with stimulating electrodes in the supraorbitary branch of the trigeminal nerve and with recording electrodes in the orbicularis oculi muscle. Computer programs were developed to quantify the appearance and evolution of eyelid conditioned responses. According to the present results, the classical conditioning of eyelid responses appears to be a suitable (associative) learning procedure to study learning capabilities in genetically-modified mice.

Are recognition deficits following occipital lobe TMS explained by raised detection thresholds?

It is known that transcranial magnetic stimulation (TMS) administered over the occipital pole suppresses recognition of visual objects. Our aim was to ascertain whether this suppression can be interpreted as a change in visual contrast threshold. Four subjects detected the orientation of an U-shaped hook flashed for 21 ms. Under control conditions, mean contrast threshold was found at 0.88 log units Weber contrast. Thresholds were raised if TMS was applied 40-200 ms after the visual stimulus. Maximum elevation was 1.67 log units under TMS at 120 ms stimulus onset asynchrony. This phenomenon can be interpreted as a reduction in signal-to-noise ratio of the visual stimuli by TMS, which can be compensated for by increasing the contrast of the stimuli.

Selective activity enhancement and persistence in weanling rats after hippocampal X-irradiation in infancy: possible relevance for ADHD.

We examined the effects of focal X-irradiation of the hippocampus in infancy on the partial reinforcement extinction effect (PREE) in weanling rats in a runway and on running wheel activity at 40 days of age. Our results show a dose-dependent X-irradiation-related reduction in granule cell neurogenesis. Weanling rats showed a corresponding increase in running speed in both acquisition and extinction and a dose-dependent reduction in the PREE--an increase in persistence after CRF and a decrease in persistence after PRF training. The same degree of hippocampal granule cell agenesis had no effect on running wheel activity. These results suggest that the enhanced speeds in the runway are incentive-related and do not reflect simple hyperactivity but rather hyperreactivity. The discussion of these results is in part a speculation regarding their possible relation to some explanations of attention deficit-hyperactivity disorder in children.

[A quantitative validation of the patterns determining the changes in higher nervous activity after irradiation with heavy charged particles under conditions of the influence of stress factors]. / Kolichestvennoe obosnovanie zakonomernostei, opredeliaiushchikh izmeneniia vysshei nervnoi deiatel'nosti posle oblucheniia tiazhelymi zariazhennymi chastitsami v usloviiakh vliianiia stressornykh faktorov.

The major regularities that govern the alteration of the higher nervous activities after irradiation with heavy charged particles have been grounded quantitatively. The influence of the environmental factors on the exposed organism acquires a stress nature and is accompanied by the alteration of the central-central and central-peripheric relationships in major nervous processes whose pathogenesis is determined, to some extent, by a change in the homeostatic level of the synaptic energy transfer rate that depends quantitatively on the response of the irradiated organism at different stages of the development of radiation damage. The rate of the synaptic transfer at early periods of radiation damage development is 11.6, 9.7, and 12.4 (relative units) corresponding to the stages of radiation affection by heavy charged particles which permits to compare qualitatively and quantitatively the reactions of final acceptors of various executive morphofunctional structures after irradiation with heavy charged particles.

[The acute extinction of orientational-exploratory activity in rats in the early periods after irradiation with high-energy helium ions]. / Issledovanie ostrogo ugasheniia orientirovochno-issledovatel'skoi aktivnosti krys v rannie sroki posle oblucheniia vysokoénergetichnymi ionami geliia.

Study of orienting-investigatory activity level, presence of grooming, manifestation of experimental neurosis, changes of rats motor activity after irradiation by helium ions in the beginning and at the end of the test at initial testing (using Dombrovskaia's maze) and also at repeated presentations with short time intervals, relation of latency and time of locomotor reaction revealed differences in the character of changes of correlation and intensity of nervous processes at different levels of doses: strengthening of inhibition processes at higher mid-lethal dose with a sharp increase of the CNS excitability and deficiency of internal inhibition process in the case of repeated presentations of the test.