Chemotherapy-Induced Cognitive Impairment and Hippocampal Neurogenesis: A Review of Physiological Mechanisms and Interventions.

A wide range of cognitive deficits, including memory loss associated with hippocampal dysfunction, have been widely reported in cancer survivors who received chemotherapy. Changes in both white matter and gray matter volume have been observed following chemotherapy treatment, with reduced volume in the medial temporal lobe thought to be due in part to reductions in hippocampal neurogenesis. Pre-clinical rodent models confirm that common chemotherapeutic agents used to treat various forms of non-CNS cancers reduce rates of hippocampal neurogenesis and impair performance on hippocampally-mediated learning and memory tasks. We review the pre-clinical rodent literature to identify how various chemotherapeutic drugs affect hippocampal neurogenesis and induce cognitive impairment. We also review factors such as physical exercise and environmental stimulation that may protect against chemotherapy-induced neurogenic suppression and hippocampal neurotoxicity. Finally, we review pharmacological interventions that target the hippocampus and are designed to prevent or reduce the cognitive and neurotoxic side effects of chemotherapy.

Deep brain stimulation of the ventromedial prefrontal cortex causes reorganization of neuronal processes and vasculature.

BACKGROUND: Chronic high-frequency electrical deep brain stimulation (DBS) of the subcallosal cingulate region is currently being investigated clinically as a therapy for treatment of refractory depression. Experimental DBS of the homologous region, the ventromedial prefrontal cortex (VMPFC), in rodent models has previously demonstrated anti-depressant-like effects. Our goal was to determine if structural remodeling accompanies the alterations of brain function previously observed as a result of chronic DBS. METHODS: Here we applied 6h of high-frequency bilateral VMPFC DBS daily to 8 9-week old C57Bl/6 mice for 5days. We investigated the "micro-lesion" effect by using a sham stimulation group (8 mice) and a control group (8 mice with a hole drilled into the skull only). Whole brain anatomy was investigated post-mortem using high-resolution magnetic resonance imaging and areas demonstrating volumetric expansion were further investigated using histology and immunohistochemistry. RESULTS: The DBS group demonstrated bilateral increases in whole hippocampus and the left thalamus volume compared to both sham and control groups. Local hippocampal and thalamic volume increases were also observed at the voxel-level; however these increases were observed in both DBS and sham groups. Follow-up immunohistochemistry in the hippocampus revealed DBS increased blood vessel size and synaptic density relative to the control group whereas the sham group demonstrated increased astrocyte size. CONCLUSIONS: Our work demonstrates that DBS not only works by altering function with neural circuits, but also by structurally altering circuits at the cellular level. Neuroplastic alterations may play a role in mediating the clinical efficacy of DBS therapy.

Potential neuroprotective role of transforming growth factor ß1 (TGFß1) in the brain.

TGFß1 is a growth factor that is known to be expressed in most neurodegenerative diseases and after vascular accidents in the brain. TGFß1 downregulates the activity of activated microglia and promotes astrogliosis. It also prevents cell death by a known mechanism dependant on astrocytes and the secretion of the plasminogen activator inhibitor 1 (PAI-1). This mechanism can provide light on what is the mechanism of action of TGFß1 as a protective factor and it can provide the pharmacological principles in which this pathway could be used with therapeutic purposes. TGFß1 is upregulated in most neurodegenerative diseases, however, its expression appears dramatically blocked in Huntington's disease, the fastest of those diseases in progress after the onset. This fact suggests that TGFß1 slows down the neurodegenerative process, preventing tissue damage and neural apoptotic death. However, the exact details of TGFß1 action are still unknown and the physiological roles on the diseases are still mysterious. Interestingly, all the data regarding the roles of TGFß1 in health and disease have been also confirmed with the use of transgenic knockouts and TGFß1 overexpressing mice. What possibly came as a surprise from the study of TGFß1 overexpressing models is that combining its neuroprotective and antiproliferative effects, this cytokine generates a significant disruption in the hippocampal circuitry with its consequent learning and memory deficit.

Intrauterine and early-life malnutrition in rats disrupts the circadian rhythm programming of energy metabolites through adulthood.

Maternal malnutrition plays a crucial role in functional development, resulting in behavioral, cognitive, and metabolic abnormalities and disturbances. "Cafeteria diet" has been linked to obesity, metabolic syndrome, diabetes, and other metabolic disruptions in the mammalian lifespan. However, there are very few reports about the effect of intrauterine and early postnatal malnutrition on the circadian rhythm programming of energy metabolites. In mammals, circadian rhythm central control is fundamental for correct interaction with the environment and physiological regulation. Exposure to malnutrition during development imprints metabolic programming throughout life on the central nervous system and peripheral systems. Lifespan studies exploring the effect of high fat/low protein diet administered during critical periods of development are scarce. The present study explored the effect of intrauterine and perinatal malnutrition induced by a high fat/low protein diet (Cafeteria Diet) on circadian and peripheral oscillators controlling glucose, insulin, and triglycerides in rats at 40 and 90 days of age. We evaluated plasma glucose and triglyceride levels in 6 Zeitgeber times, in addition to an intraperitoneal glucose tolerance test (IpTGT) and homeostasis model assessment of insulin resistance (HOMA-IR) at two time-points over 24h. Our results show that offspring of malnourished dams fed cafeteria diet present alterations in circadian rhythmicity of glucose and triglycerides associated with a change in glucose tolerance and insulin sensibility differentially regulated at the development stage and time of day. Intrauterine and early malnutrition due to a cafeteria diet produces maladaptive responses and programs energetic metabolism at several developmental stages during the lifespan.

Age-dependent effects of hippocampal neurogenesis suppression on spatial learning.

Reducing hippocampal neurogenesis sometimes, but not always, disrupts hippocampus-dependent learning and memory. Here, we tested whether animal age, which regulates rate of hippocampal neurogenesis, is a factor that influences whether deficits in spatial learning are observed after reduction of neurogenesis. We found that suppressing the generation of new hippocampal neurons via treatment with temozolomide, an antiproliferation agent, impaired learning the location of a hidden platform in the water maze in juvenile mice (1-2 months old) but not in adult mice (2-3 months old) or middle-aged mice (11-12 months old). These findings suggest that during juvenility, suppression of neurogenesis may alter hippocampal development, whereas during adulthood and aging, pre-existing neurons may compensate for the lack of new hippocampal neurons.

Chronic over-expression of TGFß1 alters hippocampal structure and causes learning deficits.

The cytokine transforming growth factor ß1 (TGFß1) is chronically upregulated in several neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jacob disease, amyotrophic lateral sclerosis and multiple sclerosis, and following stroke. Although previous studies have shown that TGFß1 may be neuroprotective, chronic exposure to elevated levels of this cytokine may contribute to disease pathology on its own. In order to study the effects of chronic exposure to TGFß1 in isolation, we used transgenic mice that over-express a constitutively active porcine TGFß1 in astrocytes. We found that TGFß1 over-expression altered brain structure, with the most pronounced volumetric increases localized to the hippocampus. Within the dentate gyrus (DG) of the hippocampus, increases in granule cell number and astrocyte size were responsible for volumetric expansion, with the increased granule cell number primarily related to a marked reduction in death of new granule cells generated in adulthood. Finally, these cumulative changes in DG microstructure and macrostructure were associated with the age-dependent emergence of spatial learning deficits in TGFß1 over-expressing mice. Together, our data indicate that chronic upregulation of TGFß1 negatively impacts hippocampal structure and, even in the absence of disease, impairs hippocampus-dependent learning.

Hippocampal neurogenesis facilitates cognitive flexibility in a fear discrimination task.

Hippocampal neurogenesis, the continuous creation of new neurons in the adult brain, influences memory, regulates the expression of defensive responses to threat (fear), and cognitive processes like pattern separation and behavioral flexibility. One hypothesis proposes that neurogenesis promotes cognitive flexibility by degrading established memories and promoting relearning. Yet, empirical evidence on its role in fear discrimination tasks is scarce. In this study, male rats were initially trained to differentiate between two similar environments, one associated with a threat. Subsequently, we enhanced neurogenesis through environmental enrichment and memantine treatments. We then reversed the emotional valence of these contexts. In both cases, neurogenesis improved the rats' ability to relearn the aversive context. Interestingly, we observed increased hippocampal activity, and decreased activity in the prelimbic cortex and lateral habenula, while the infralimbic cortex remained unchanged, suggesting neurogenesis-induced plasticity changes in this brain network. Moreover, when we pharmacologically inhibited the increased neurogenesis with Methotrexate, rats struggled to relearn context discrimination, confirming the crucial role of neurogenesis in this cognitive process. Overall, our findings highlight neurogenesis's capacity to facilitate changes in fear discrimination and emphasize the involvement of a prefrontal-hippocampal-habenula mechanism in this process. This study emphasizes the intricate relationship between hippocampal neurogenesis, cognitive flexibility, and the modulation of fear-related memories.

Olfactory neurogenesis and its role in fear memory modulation.

Olfaction is a critical sense that allows animals to navigate and understand their environment. In mammals, the critical brain structure to receive and process olfactory information is the olfactory bulb, a structure characterized by a laminated pattern with different types of neurons, some of which project to distant telencephalic structures, like the piriform cortex, the amygdala, and the hippocampal formation. Therefore, the olfactory bulb is the first structure of a complex cognitive network that relates olfaction to different types of memory, including episodic memories. The olfactory bulb continuously adds inhibitory newborn neurons throughout life; these cells locate both in the granule and glomerular layers and integrate into the olfactory circuits, inhibiting projection neurons. However, the roles of these cells modulating olfactory memories are unclear, particularly their role in fear memories. We consider that olfactory neurogenesis might modulate olfactory fear memories by a plastic process occurring in the olfactory bulb.

Maternal enrichment increases infantile spatial amnesia mediated by postnatal neurogenesis modulation.

Infantile amnesia, the inability to form long-lasting episodic memories, is a phenomenon extensively known but with no clear understanding of its origins. However, a recent study showed that high rates of hippocampal postnatal neurogenesis degrade episodic-like memories in infants a few days after memory acquisition. Additionally, new studies indicate that exposure to an enriched environment in mice leads to high hippocampal neurogenesis in their offspring. Nevertheless, it is still unclear how this intergenerational trait affects the persistence of hippocampal memories. Therefore, we evaluated spatial memory retention in the offspring of enriched female mice after weaning to address this question. Ten days after spatial learning, we tested memory retention, observing that the offspring of enriched dams increased spatial memory failure; this finding correlates with high proliferation rates in the hippocampus. Furthermore, we evaluated the causal relationship between postnatal hippocampal neurogenesis and memory failure using the antiproliferative drug Temozolomide (TMZ), which rescued spatial memory retrieval. Finally, we evaluated neuronal activity in the hippocampus quantifying the cells expressing the immediate early gene c-Fos. This evaluation showed engram modifications between groups. This neural activity pattern indicates that the high neurogenesis rates can modify memory engrams and cognitive performance. In conclusion, the inherited increase of hippocampal neurogenesis by enriched dams leads to plastic changes that exacerbate infantile amnesia in a spatial task.

Maze training in mice induces MRI-detectable brain shape changes specific to the type of learning.

Multiple recent human imaging studies have suggested that the structure of the brain can change with learning. To investigate the mechanism behind such structural plasticity, we sought to determine whether maze learning in mice induces brain shape changes that are detectable by MRI and whether such changes are specific to the type of learning. Here we trained inbred mice for 5 days on one of three different versions of the Morris water maze and, using high-resolution MRI, revealed specific growth in the hippocampus of mice trained on a spatial variant of the maze, whereas mice trained on the cued version were found to have growth in the striatum. The structure-specific growth found furthermore correlated with GAP-43 staining, a marker of neuronal process remodelling, but not with neurogenesis nor neuron or astrocyte numbers or sizes. Our findings provide evidence that brain morphology changes rapidly at a scale detectable by MRI and furthermore demonstrate that specific brain regions grow or shrink in response to the changing environmental demands. The data presented herein have implications for both human imaging as well as rodent structural plasticity research, in that it provides a tool to screen for neuronal plasticity across the whole brain in the mouse while also providing a direct link between human and mouse studies.

Functional convergence of developmentally and adult-generated granule cells in dentate gyrus circuits supporting hippocampus-dependent memory.

In the hippocampus, the production of dentate granule cells (DGCs) persists into adulthood. As adult-generated neurons are thought to contribute to hippocampal memory processing, promoting adult neurogenesis therefore offers the potential for restoring mnemonic function in the aged or diseased brain. Within this regenerative context, one key issue is whether developmentally generated and adult-generated DGCs represent functionally equivalent or distinct neuronal populations. To address this, we labeled separate cohorts of developmentally generated and adult-generated DGCs and used immunohistochemical approaches to compare their integration into circuits supporting hippocampus-dependent memory in intact mice. First, in the water maze task, rates of integration of adult-generated DGCs were regulated by maturation, with maximal integration not occurring until DGCs were five or more weeks in age. Second, these rates of integration were equivalent for embryonically, postnatally, and adult-generated DGCs. Third, these findings generalized to another hippocampus-dependent task, contextual fear conditioning. Together, these experiments indicate that developmentally generated and adult-generated DGCs are integrated into hippocampal memory networks at similar rates, and suggest a functional equivalence between DGCs generated at different developmental stages.

Hippocampal neurogenesis regulates recovery of defensive responses by recruiting threat- and extinction-signalling brain networks.

Safe exposure to a context that was previously associated with threat leads to extinction of defensive responses. Such contextual fear extinction involves the formation of a new memory that inhibits a previously acquired contextual fear memory. However, fear-related responses often return with the simple passage of time (spontaneous fear recovery). Given that contextual fear and extinction memories are hippocampus-dependent and hippocampal neurogenesis has been reported to modify preexisting memories, we hypothesized that neurogenesis-mediated modification of preexisting extinction memory would modify spontaneous fear recovery. To test this, rats underwent contextual fear conditioning followed by extinction. Subsequently, we exposed rats to an enriched environment or focal X-irradiation to enhance or ablate hippocampal neurogenesis, respectively. Over a month later, rats were tested to evaluate spontaneous fear recovery. We found that enhancing neurogenesis after, but not before, extinction prevented fear recovery. In contrast, neurogenesis ablation after, but not before, extinction promoted fear recovery. Using the neuronal activity marker c-Fos, we identified brain regions recruited in these opposing neurogenesis-mediated changes during fear recovery. Together, our findings indicate that neurogenesis manipulation after extinction learning modifies fear recovery by recruiting brain network activity that mediates the expression of preexisting contextual fear and extinction memories.

Hippocampal neurogenesis regulates forgetting during adulthood and infancy.

Throughout life, new neurons are continuously added to the dentate gyrus. As this continuous addition remodels hippocampal circuits, computational models predict that neurogenesis leads to degradation or forgetting of established memories. Consistent with this, increasing neurogenesis after the formation of a memory was sufficient to induce forgetting in adult mice. By contrast, during infancy, when hippocampal neurogenesis levels are high and freshly generated memories tend to be rapidly forgotten (infantile amnesia), decreasing neurogenesis after memory formation mitigated forgetting. In precocial species, including guinea pigs and degus, most granule cells are generated prenatally. Consistent with reduced levels of postnatal hippocampal neurogenesis, infant guinea pigs and degus did not exhibit forgetting. However, increasing neurogenesis after memory formation induced infantile amnesia in these species.

Increased transforming growth factor-ß1 modulates glutamate receptor expression in the hippocampus.

Transforming growth factor-beta 1 (TGF-ß1) is an inflammation-related cytokine. Its expression in the brain increases under conditions of neurodegenerative diseases and injuries. Previous studies have shown that genomic alterations of TGF-ß1 expression in the brain cause neurodegenerative changes in aged mice. The present study revealed that increased production of TGF-ß1 in transgenic mice resulted in gliosis at young ages. In addition, the increased TGF-ß1 augmented the expression of some key subunits of α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the hippocampus. Treatment of cultured hippocampal neurons with TGF-ß1 facilitated neurite outgrowth and enhanced glutamate-evoked currents. Together, these data suggest that increased TGF-ß1 alters ionotropic glutamate receptor expression and function in the hippocampus.

Neonatal inflammatory pain increases hippocampal neurogenesis in rat pups.

Preterm infants undergo several painful procedures during their stay in neonatal intensive care units. Previous studies suggest that early painful experiences may have an impact on brain development. Here, we used an animal model to investigate the effect of neonatal pain on the generation of new neurons in the dentate gyrus region of the hippocampus. Rat pups received intraplantar injections of complete Freund's adjuvant (CFA), a painful inflammatory agent, on either P1 or P8 and were sacrificed on P22. We found that rat pups injected with CFA on P8 had more BrdU-labeled cells and a higher density of cells expressing doublecortin (DCX) in the subgranular zone of the dentate gyrus. No change in BrdU-labeling or DCX expression was observed in pups injected with CFA on P1. These findings indicate that neonatal pain can increase hippocampal neurogenesis, suggesting that early painful experiences may shape brain development and thereby influence behavioral outcome.

Effect of growth hormone on Cyclooxygenase-2 expression in the hippocampus of rats chronically exposed to ozone.

The aim of this study was to determine GH-effects on Cyclooxygenase-2 (COX-2) expression on hippocampus alterations caused by ozone exposure. Seventy male rats were divided into: (1) control; (2) exposed to ozone for 7, 15, and 30 days; (3) exposed to ozone and treated with GH, for 7, 15, and 30 days. Results showed that lipoperoxidation levels and number of COX-2-positive cells increased in all groups exposed to ozone compared to control. In the groups treated with GH, COX-2 immunoreactive cell number decreased with respect to the ozone group. Therefore, GH could provide protection against damage induced by oxidative stress.