Chronic ultraviolet irradiation induces memory deficits via dysregulation of the dopamine pathway.

The effects of ultraviolet (UV) radiation on brain function have previously been investigated; however, the specific neurotransmitter-mediated mechanisms responsible for UV radiation-induced neurobehavioral changes remain elusive. In this study, we aimed to explore the mechanisms underlying UV radiation-induced neurobehavioral changes. In a mouse model, we observed that UV irradiation of the skin induces deficits in hippocampal memory, synaptic plasticity, and adult neurogenesis, as well as increased dopamine levels in the skin, adrenal glands, and brain. Chronic UV exposure altered the expression of genes involved in dopaminergic neuron differentiation. Furthermore, chronic peripheral dopamine treatments resulted in memory deficits. Systemic administration of a dopamine D1/D5 receptor antagonist reversed changes in memory, synaptic plasticity, adult neurogenesis, and gene expression in UV-irradiated mice. Our findings provide converging evidence that chronic UV exposure alters dopamine levels in the central nervous system and peripheral organs, including the skin, which may underlie the observed neurobehavioral shifts, such as hippocampal memory deficits and impaired neurogenesis. This study underscores the importance of protection from UV exposure and introduces the potential of pharmacological approaches targeting dopamine receptors to counteract the adverse neurological impacts of UV exposure.

Extracellular vesicles from GABAergic but not glutamatergic neurons protect against neurological dysfunction following cranial irradiation.

Cranial irradiation used to control brain malignancies invariably leads to progressive and debilitating declines in cognition. Clinical efforts implementing hippocampal avoidance and NMDAR antagonism, have sought to minimize dose to radiosensitive neurogenic regions while normalizing excitatory/inhibitory (E/I) tone. Results of these trials have yielded only marginal benefits to cognition, prompting current studies to evaluate the potential of systemic extracellular vesicle (EV) therapy to restore neurocognitive functionality in the irradiated brain. Here we tested the hypothesis that EVs derived from inhibitory but not excitatory neuronal cultures would prove beneficial to cognition and associated pathology. Rats subjected to a clinically relevant, fractionated cranial irradiation paradigm were given multiple injections of either GABAergic- or glutamatergic-derived EV and subjected to behavioral testing. Rats treated with GABAergic but not glutamatergic EVs showed significant improvements on hippocampal- and cortical-dependent behavioral tasks. While each treatment enhanced levels of the neurotrophic factors BDNF and GDNF, only GABAergic EVs preserved granule cell neuron dendritic spine density. Additional studies conducted with GABAergic EVs, confirmed significant benefits on amygdala-dependent behavior and modest changes in synaptic plasticity as measured by long-term potentiation. These data point to a potentially more efficacious approach for resolving radiation-induced neurological deficits, possibly through a mechanism able to restore homeostatic E/I balance.

Partial-Brain Radiation-Induced Microvascular Cognitive Impairment in Juvenile Murine Unilateral Hippocampal Synaptic Plasticity.

PURPOSE: Radiation-induced cognitive deficits have a severe negative impact on pediatric brain tumor patients. The severity of cognitive symptoms is related to the age of the child when radiation was applied, with the most severe effects seen in the youngest. Previous studies using whole-brain irradiation in mice confirmed these findings. To understand ipsilateral and contralateral changes in the hippocampus after partial-brain radiation therapy (PBRT) of the left hemisphere, we assessed the neuroplasticity and changes in the microvasculature of the irradiated and nonirradiated hippocampus in juvenile mice. METHODS AND MATERIALS: The left hemispheres of 5-week-old mice were irradiated with 2, 8, and 20 Gy and a fractionated dose of 8 Gy in 2 fractions using a computed tomography image guided small animal radiation research platform. Long-term potentiation (LTP) has been monitored ex vivo in the hippocampal cornu ammonis 1 (CA1) region and was assessed 3 days and 5 and 10 weeks after PBRT in both hemispheres and compared to a sham group. Irradiation effects on the hippocampus microvasculature were quantified by efficient tissue clearing and multiorgan volumetric imaging. RESULTS: LTP in irradiated hippocampal slices of juvenile mice declines 3 days after radiation, lasts up to 10 weeks in the irradiated part of the hippocampus, and correlates with a significantly reduced microvasculature length. Specifically, LTP inhibition is sustained in the irradiated (20 Gy, 8 Gy in 2 fractions, 8 Gy, 2 Gy) hippocampus, whereas the contralateral hippocampus remains unaffected after PBRT. LTP inhibition in the irradiated hemisphere after PBRT might be associated with an impaired microvascular network. CONCLUSION: PBRT induces a long-lasting impairment in neuroplasticity and the microvessel network of the irradiated hippocampus, whereas the contralateral hippocampus remains unaffected. These findings provide insight into the design of PBRT strategies to better protect the young developing brain from cognitive decline.

Induction of Human Motor Cortex Plasticity by Theta Burst Transcranial Ultrasound Stimulation.

OBJECTIVE: Transcranial ultrasound stimulation (TUS) is a promising noninvasive brain stimulation technique with advantages of high spatial precision and ability to target deep brain regions. This study aimed to develop a TUS protocol to effectively induce brain plasticity in human subjects. METHODS: An 80-second train of theta burst patterned TUS (tbTUS), regularly patterned TUS (rTUS) with the same sonication duration, and sham tbTUS was delivered to the motor cortex in healthy subjects. Transcranial magnetic stimulation (TMS) was used to examine changes in corticospinal excitability, intracortical inhibition and facilitation, and the site of plasticity induction. The effects of motor cortical tbTUS on a visuomotor task and the effects of occipital cortex tbTUS on motor cortical excitability were also tested. RESULTS: The tbTUS produced consistent increase in corticospinal excitability for at least 30 minutes, whereas rTUS and sham tbTUS produced no significant change. tbTUS decreased short-interval intracortical inhibition and increased intracortical facilitation. The effects of TMS in different current directions suggested that the site of the plastic changes was within the motor cortex. tbTUS to the occipital cortex did not change motor cortical excitability. Motor cortical tbTUS shortened movement time in a visuomotor task. INTERPRETATION: tbTUS is a novel and efficient paradigm to induce cortical plasticity in humans. It has the potential to be developed for neuromodulation treatment for neurological and psychiatric disorders, and to advance neuroscience research. ANN NEUROL 2022;91:238-252.

The retinal ipRGC-preoptic circuit mediates the acute effect of light on sleep.

Light regulates daily sleep rhythms by a neural circuit that connects intrinsically photosensitive retinal ganglion cells (ipRGCs) to the circadian pacemaker, the suprachiasmatic nucleus. Light, however, also acutely affects sleep in a circadian-independent manner. The neural circuits involving the acute effect of light on sleep remain unknown. Here we uncovered a neural circuit that drives this acute light response, independent of the suprachiasmatic nucleus, but still through ipRGCs. We show that ipRGCs substantially innervate the preoptic area (POA) to mediate the acute light effect on sleep in mice. Consistently, activation of either the POA projecting ipRGCs or the light-responsive POA neurons increased non-rapid eye movement (NREM) sleep without influencing REM sleep. In addition, inhibition of the light-responsive POA neurons blocked the acute light effects on NREM sleep. The predominant light-responsive POA neurons that receive ipRGC input belong to the corticotropin-releasing hormone subpopulation. Remarkably, the light-responsive POA neurons are inhibitory and project to well-known wakefulness-promoting brain regions, such as the tuberomammillary nucleus and the lateral hypothalamus. Therefore, activation of the ipRGC-POA circuit inhibits arousal brain regions to drive light-induced NREM sleep. Our findings reveal a functional retina-brain circuit that is both necessary and sufficient for the acute effect of light on sleep.

Acute, Low-Dose Neutron Exposures Adversely Impact Central Nervous System Function.

A recognized risk of long-duration space travel arises from the elevated exposure astronauts face from galactic cosmic radiation (GCR), which is composed of a diverse array of energetic particles. There is now abundant evidence that exposures to many different charged particle GCR components within acute time frames are sufficient to induce central nervous system deficits that span from the molecular to the whole animal behavioral scale. Enhanced spacecraft shielding can lessen exposures to charged particle GCR components, but may conversely elevate neutron radiation levels. We previously observed that space-relevant neutron radiation doses, chronically delivered at dose-rates expected during planned human exploratory missions, can disrupt hippocampal neuronal excitability, perturb network long-term potentiation and negatively impact cognitive behavior. We have now determined that acute exposures to similar low doses (18 cGy) of neutron radiation can also lead to suppressed hippocampal synaptic signaling, as well as decreased learning and memory performance in male mice. Our results demonstrate that similar nervous system hazards arise from neutron irradiation regardless of the exposure time course. While not always in an identical manner, neutron irradiation disrupts many of the same central nervous system elements as acute charged particle GCR exposures. The risks arising from neutron irradiation are therefore important to consider when determining the overall hazards astronauts will face from the space radiation environment.

Microglia enable mature perineuronal nets disassembly upon anesthetic ketamine exposure or 60-Hz light entrainment in the healthy brain.

Perineuronal nets (PNNs), components of the extracellular matrix, preferentially coat parvalbumin-positive interneurons and constrain critical-period plasticity in the adult cerebral cortex. Current strategies to remove PNN are long-lasting, invasive, and trigger neuropsychiatric symptoms. Here, we apply repeated anesthetic ketamine as a method with minimal behavioral effect. We find that this paradigm strongly reduces PNN coating in the healthy adult brain and promotes juvenile-like plasticity. Microglia are critically involved in PNN loss because they engage with parvalbumin-positive neurons in their defined cortical layer. We identify external 60-Hz light-flickering entrainment to recapitulate microglia-mediated PNN removal. Importantly, 40-Hz frequency, which is known to remove amyloid plaques, does not induce PNN loss, suggesting microglia might functionally tune to distinct brain frequencies. Thus, our 60-Hz light-entrainment strategy provides an alternative form of PNN intervention in the healthy adult brain.

Comparison of ELF-EMFs stimulation with current stimulation on the regulation of LTP of SC-CA1 synapses in young rat hippocampus.

BACKGROUND: Long-term potentiation (LTP) is an important functional indicator for synaptic plasticity. Extremely low frequency electromagnetic fields (ELF-EMFs) are a physical means to regulate LTP, which induce induced currents. It is unknown whether induced current is the key factor when LTP is regulated by ELF-EMFs.New Method: A method is proposed for calculating the current value induced by ELF-EMFs. Then, a comparison of ELF-EMFs with current on the regulation of theta-burst or high-frequency stimulation (TBS/HFS)-LTP was performed. RESULTS: The LTP after ELF-EMFs and µA current regulation was significantly reduced. The regulatory effect of 0.1 µA current on LTP was similar with 100 Hz/2 mT ELF-EMFs, while 0.2 µA had a stronger regulatory effect than 200 Hz/2 mT on HFS-LTP.Comparison with Existing Methods: Most of the existing methods were used to calculate the induced current in human models, while we present a more accurate model for calculating the induced current induced by ELF-EMFs in the rat brain slices. CONCLUSIONS: This work indicated that µA current and ELF-EMFs stimulation reduced LTP. Also, we demonstrated that the regulatory effect of ELF-EMFs on LTP is not entirely deriving from the induced current, since its magnetic mechanism might have played a certain role.

Chronic Low Dose Neutron Exposure Results in Altered Neurotransmission Properties of the Hippocampus-Prefrontal Cortex Axis in Both Mice and Rats.

The proposed deep space exploration to the moon and later to Mars will result in astronauts receiving significant chronic exposures to space radiation (SR). SR exposure results in multiple neurocognitive impairments. Recently, our cross-species (mouse/rat) studies reported impaired associative memory formation in both species following a chronic 6-month low dose exposure to a mixed field of neutrons (1 mGy/day for a total dose pf 18 cGy). In the present study, we report neutron exposure induced synaptic plasticity in the medial prefrontal cortex, accompanied by microglial activation and significant synaptic loss in the hippocampus. In a parallel study, neutron exposure was also found to alter fluorescence assisted single synaptosome LTP (FASS-LTP) in the hippocampus of rats, that may be related to a reduced ability to insert AMPAR into the post-synaptic membrane, which may arise from increased phosphorylation of the serine 845 residue of the GluA1 subunit. Thus, we demonstrate for the first time, that low dose chronic neutron irradiation impacts homeostatic synaptic plasticity in the hippocampal-cortical circuit in two rodent species, and that the ability to successfully encode associative recognition memory is a dynamic, multicircuit process, possibly involving compensatory changes in AMPAR density on the synaptic surface.

Systemic HDAC3 inhibition ameliorates impairments in synaptic plasticity caused by simulated galactic cosmic radiation exposure in male mice.

Deep space travel presents a number of measurable risks including exposure to a spectrum of radiations of varying qualities, termed galactic cosmic radiation (GCR) that are capable of penetrating the spacecraft, traversing through the body and impacting brain function. Using rodents, studies have reported that exposure to simulated GCR leads to cognitive impairments associated with changes in hippocampus function that can persist as long as one-year post exposure with no sign of recovery. Whether memory can be updated to incorporate new information in mice exposed to GCR is unknown. Further, mechanisms underlying long lasting impairments in cognitive function as a result of GCR exposure have yet to be defined. Here, we examined whether whole body exposure to simulated GCR using 6 ions and doses of 5 or 30 cGy interfered with the ability to update an existing memory or impact hippocampal synaptic plasticity, a cellular mechanism believed to underlie memory processes, by examining long term potentiation (LTP) in acute hippocampal slices from middle aged male mice 3.5-5 months after radiation exposure. Using a modified version of the hippocampus-dependent object location memory task developed by our lab termed "Objects in Updated Locations" (OUL) task we find that GCR exposure impaired hippocampus-dependent memory updating and hippocampal LTP 3.5-5 months after exposure. Further, we find that impairments in LTP are reversed through one-time systemic subcutaneous injection of the histone deacetylase 3 inhibitor RGFP 966 (10 mg/kg), suggesting that long lasting impairments in cognitive function may be mediated at least in part, through epigenetic mechanisms.

Activation of Neural Modeling-Related Genes in the Heart of Mice after Gamma Irradiation.

OBJECTIVE: Radiation-induced heart disease (RIHD) is a common sequela of thoracic irradiation. At the same time, nerve remodeling is involved in the progression of heart disease. However, the activation of the nerve remodeling related genes in radiation-induced heart disease is still lacking. METHODS: In this study, C57BL/J mice was anesthetized by intraperitoneal injection with pentobarbital sodium (2%, 40 mg/kg), and radiation was delivered using a cobalt-60 (60Co) teletherapy unit (Cirus). When the mice were anesthetized, none of them showed the signs of peritonitis, pain, or discomfort. The mice hearts were exposed to a γ-radiation field of 5 mm × 5 mm. The total dose of γ-radiation was 3 Gy/day for each animal for 5 consecutive days. The mice were executed by severed neck, and its limbs were weak. Quantitative Polymerase Chain Reaction (qPCR) and immunohistochemistry were used to explore the possible mechanism of arrhythmia in patients with RIHD. RESULTS: Our results demonstrated that Growth-Associated Protein 43 (GAP43) was increased significantly after radioactive heart injury compared with the control group. Moreover, the protein expression of Tyrosine hydroxylase (TH) and Choline acetyl-transferase (CHAT) was significantly decreased compared with the control group and gradually increased with time rend. The nerve growth factor (NGF) was remarkably increased after radiation-induced heart injury compared with the control group. Immunohistochemistry results indicated that the nerve growth factors GAP43 and NGF were significantly increased after radiation-induced heart injury. CONCLUSIONS: Chest radiotherapy could activate the neural modeling related genes in RIHD. This may provide a new treatment plan for the future treatment of heart problems caused by chest radiotherapy.

Light-induced engagement of microglia to focally remodel synapses in the adult brain.

Microglia continuously monitor synapses, but active synaptic remodeling by microglia in mature healthy brains is rarely directly observed. We performed targeted photoablation of single synapses in mature transgenic mice expressing fluorescent labels in neurons and microglia. The photodamage focally increased the duration of microglia-neuron contacts, and dramatically exacerbated both the turnover of dendritic spines and presynaptic boutons as well as the generation of new filopodia originating from spine heads or boutons. The results of microglia depletion confirmed that elevated spine turnover and the generation of presynaptic filopodia are microglia-dependent processes.

Artificial Light at Night Increases Recruitment of New Neurons and Differentially Affects Various Brain Regions in Female Zebra Finches.

Despite growing evidence that demonstrate adverse effects of artificial light at night (ALAN) on many species, relatively little is known regarding its effects on brain plasticity in birds. We recently showed that although ALAN increases cell proliferation in brains of birds, neuronal densities in two brain regions decreased, indicating neuronal death, which might be due to mortality of newly produced neurons or of existing ones. Therefore, in the present study we studied the effect of long-term ALAN on the recruitment of newborn neurons into their target regions in the brain. Accordingly, we exposed zebra finches (Taeniopygia guttata) to 5 lux ALAN, and analysed new neuronal recruitment and total neuronal densities in several brain regions. We found that ALAN increased neuronal recruitment, possibly as a compensatory response to ALAN-induced neuronal death, and/or due to increased nocturnal locomotor activity caused by sleep disruption. Moreover, ALAN also had a differential temporal effect on neuronal densities, because hippocampus was more sensitive to ALAN and its neuronal densities were more affected than in other brain regions. Nocturnal melatonin levels under ALAN were significantly lower compared to controls, indicating that very low ALAN intensities suppress melatonin not only in nocturnal, but also in diurnal species.

Brain irradiation leads to persistent neuroinflammation and long-term neurocognitive dysfunction in a region-specific manner.

Long-term cognitive deficits are observed after treatment of brain tumors or metastases by radiotherapy. Treatment optimization thus requires a better understanding of the effects of radiotherapy on specific brain regions, according to their sensitivity and interconnectivity. In the present study, behavioral tests supported by immunohistology and magnetic resonance imaging provided a consistent picture of the persistent neurocognitive decline and neuroinflammation after the onset of irradiation-induced necrosis in the right primary somatosensory cortex of Fischer rats. Necrosis surrounded by neovascularization was first detected 54 days after irradiation and then spread to 110 days in the primary motor cortex, primary somatosensory region, striatum and right ventricle, resulting in fiber bundle disruption and demyelination in the corpus callosum of the right hemisphere. These structural damages translated into selective behavioral changes including spatial memory loss, disinhibition of anxiety-like behaviors, hyperactivity and pain hypersensitivity, but no significant alteration in motor coordination and grip strength abilities. Concomitantly, activated microglia and reactive astrocytes, accompanied by infiltration of leukocytes (CD45+) and T-cells (CD3+) cooperated to shape the neuroinflammation response. Overall, our study suggests that the slow and gradual onset of cellular damage would allow adaptation in brain regions that are susceptible to neuronal plasticity; while other cerebral structures that do not have this capacity would be more affected. The planning of radiotherapy, adjusted to the sensitivity and adaptability of brain structures, could therefore preserve certain neurocognitive functions; while higher doses of radiation could be delivered to brain areas that can better adapt to this treatment. In addition, strategies to block early post-radiation events need to be explored to prevent the development of long-term cognitive dysfunction.

Modulation of Coordinated Activity across Cortical Layers by Plasticity of Inhibitory Synapses.

In the neocortex, synaptic inhibition shapes all forms of spontaneous and sensory evoked activity. Importantly, inhibitory transmission is highly plastic, but the functional role of inhibitory synaptic plasticity is unknown. In the mouse barrel cortex, activation of layer (L) 2/3 pyramidal neurons (PNs) elicits strong feedforward inhibition (FFI) onto L5 PNs. We find that FFI involving parvalbumin (PV)-expressing cells is strongly potentiated by postsynaptic PN burst firing. FFI plasticity modifies the PN excitation-to-inhibition (E/I) ratio, strongly modulates PN gain, and alters information transfer across cortical layers. Moreover, our LTPi-inducing protocol modifies firing of L5 PNs and alters the temporal association of PN spikes to γ-oscillations both in vitro and in vivo. All of these effects are captured by unbalancing the E/I ratio in a feedforward inhibition circuit model. Altogether, our results indicate that activity-dependent modulation of perisomatic inhibitory strength effectively influences the participation of single principal cortical neurons to cognition-relevant network activity.

Interleukin 10 Restores Lipopolysaccharide-Induced Alterations in Synaptic Plasticity Probed by Repetitive Magnetic Stimulation.

Systemic inflammation is associated with alterations in complex brain functions such as learning and memory. However, diagnostic approaches to functionally assess and quantify inflammation-associated alterations in synaptic plasticity are not well-established. In previous work, we demonstrated that bacterial lipopolysaccharide (LPS)-induced systemic inflammation alters the ability of hippocampal neurons to express synaptic plasticity, i.e., the long-term potentiation (LTP) of excitatory neurotransmission. Here, we tested whether synaptic plasticity induced by repetitive magnetic stimulation (rMS), a non-invasive brain stimulation technique used in clinical practice, is affected by LPS-induced inflammation. Specifically, we explored brain tissue cultures to learn more about the direct effects of LPS on neural tissue, and we tested for the plasticity-restoring effects of the anti-inflammatory cytokine interleukin 10 (IL10). As shown previously, 10 Hz repetitive magnetic stimulation (rMS) of organotypic entorhino-hippocampal tissue cultures induced a robust increase in excitatory neurotransmission onto CA1 pyramidal neurons. Furthermore, LPS-treated tissue cultures did not express rMS-induced synaptic plasticity. Live-cell microscopy in tissue cultures prepared from a novel transgenic reporter mouse line [C57BL/6-Tg(TNFa-eGFP)] confirms that ex vivo LPS administration triggers microglial tumor necrosis factor alpha (TNFα) expression, which is ameliorated in the presence of IL10. Consistent with this observation, IL10 hampers the LPS-induced increase in TNFα, IL6, IL1ß, and IFNγ and restores the ability of neurons to express rMS-induced synaptic plasticity in the presence of LPS. These findings establish organotypic tissue cultures as a suitable model for studying inflammation-induced alterations in synaptic plasticity, thus providing a biological basis for the diagnostic use of transcranial magnetic stimulation in the context of brain inflammation.

Artificial light at night affects brain plasticity and melatonin in birds.

Artificial light at night (ALAN), which disrupts the daily cycle of light, has vast biological impacts on all organisms, and is also associated with several health problems. The few existing studies on neuronal plasticity and cognitive functions in mammals indicate that a disruption of the circadian cycle impairs learning and memory and suppresses neurogenesis. However, nothing is known about the effect of ALAN on neuronal plasticity in birds. To this end, zebra finches (Taeniopygia guttata) were exposed to ecologically relevant ALAN intensities (0.5, 1.5 and 5 lx), treated with BrdU to quantify cell proliferation in their ventricular zone (VZ), and compared to controls that were kept under dark nights. We found, in our diurnal birds, that ALAN significantly increased cell proliferation in the VZ. However, neuronal densities in two brain regions decreased under ALAN, suggesting neuronal death. In addition, ALAN suppressed nocturnal melatonin production in a dose-dependent manner, and might also increase body mass. Taken together, our findings add to the notion of the deleterious effect of ALAN.

Driving Neurogenesis in Neural Stem Cells with High Sensitivity Optogenetics.

Optogenetic stimulation of neural stem cells (NSCs) enables their activity-dependent photo-modulation. This provides a spatio-temporal tool for studying activity-dependent neurogenesis and for regulating the differentiation of the transplanted NSCs. Currently, this is mainly driven by viral transfection of channelrhodopsin-2 (ChR2) gene, which requires high irradiance and complex in vivo/vitro stimulation systems. Additionally, despite the extensive application of optogenetics in neuroscience, the transcriptome-level changes induced by optogenetic stimulation of NSCs have not been elucidated yet. Here, we made transformed NSCs (SFO-NSCs) stably expressing one of the step-function opsin (SFO)-variants of chimeric channelrhodopsins, ChRFR(C167A), which is more sensitive to blue light than native ChR2, via a non-viral transfection system using piggyBac transposon. We set up a simple low-irradiance optical stimulation (OS)-incubation system that induced c-fos mRNA expression, which is activity-dependent, in differentiating SFO-NSCs. More neuron-like SFO-NCSs, which had more elongated axons, were differentiated with daily OS than control cells without OS. This was accompanied by positive/negative changes in the transcriptome involved in axonal remodeling, synaptic plasticity, and microenvironment modulation with the up-regulation of several genes involved in the Ca2+-related functions. Our approach could be applied for stem cell transplantation studies in tissue with two strengths: lower carcinogenicity and less irradiance needed for tissue penetration.

CREB Signaling Mediates Dose-Dependent Radiation Response in the Murine Hippocampus Two Years after Total Body Exposure.

The impact of low-dose ionizing radiation (IR) on the human brain has recently attracted attention due to the increased use of IR for diagnostic purposes. The aim of this study was to investigate low-dose radiation response in the hippocampus. Female B6C3F1 mice were exposed to total body irradiation with 0 (control), 0.063, 0.125, or 0.5 Gy. Quantitative label-free proteomic analysis of the hippocampus was performed after 24 months. CREB signaling and CREB-associated pathways were affected at all doses. The lower doses (0.063 and 0.125 Gy) induced the CREB pathway, whereas the exposure to 0.5 Gy deactivated CREB. Similarly, the lowest dose (0.063 Gy) was anti-inflammatory, reducing the number of activated microglia. In contrast, induction of activated microglia and reactive astroglia was found at 0.5 Gy, suggesting increased inflammation and astrogliosis, respectively. The apoptotic markers BAX and cleaved CASP-3 and oxidative stress markers were increased only at the highest dose. Since the activated CREB pathway plays a central role in learning and memory, these data suggest neuroprotection at the lowest dose (0.063 Gy) but neurodegeneration at 0.5 Gy. The response to 0.5 Gy resembles alterations found in healthy aging and thus may represent radiation-induced accelerated aging of the brain.