Taste alteration is a frequently reported side effect in patients receiving the chemotherapeutic agent, irinotecan. However, the way in which irinotecan causes taste disturbance and the type of taste ...impairment that is affected remain elusive. Here, we used the two‐bottle preference test to characterize behavioral taste responses and employed immunohistochemical analyses to clarify the types and mechanisms of taste alteration induced, in mice, by irinotecan administration. Irinotecan administration resulted in a reduced intake of sodium taste solution but had no effect on sweet taste responses, as determined in the two‐bottle preference test. In the presence of amiloride, which inhibits the function of the epithelial sodium channel (ENaC) in the periphery, the intake of sodium taste solution was comparable between the irinotecan‐treated and control groups. Immunohistochemical analyses revealed that α‐ENaC immunoreactivity detected in taste bud cells decreased slowly after irinotecan administration, and that administration of irinotecan had little effect on the number of cells expressing the cellular proliferation marker, Ki67, within or around taste buds. Our results imply that irinotecan administration may be responsible for altered behavioral sodium taste responses originating from ENaC function in the periphery, while being accompanied by the reduction of α‐ENaC expression at the apical membrane of taste receptor cells without disturbing taste cell renewal.
New neurons are continually produced after birth from neural stem/progenitor cells (NSCs/NPCs) in the hippocampal dentate gyrus (DG). Recent studies have reported that fatty acid binding protein 7 ...(Fabp7/brain lipid binding protein (BLBP)) is required for the maintenance of embryonic NSCs/NPCs and have identified an association between the Fabp7 gene and behavioral paradigms that correlate with hippocampal functions. However, the specific roles of Fabps in postnatal neurogenesis remain unknown. Herein, we demonstrate the effects of Fabp7, and another Fabp, Fabp5, on postnatal neurogenesis. Fabp7 and Fabp5 were detected in the subgranular zone (SGZ) of the DG, and Fabp7+ cells were less differentiated than Fabp5+ cells. We analyzed the differentiation state of NSCs/NPCs in the SGZ of 4-week-old (4w) Fabp7 knockout (7KO), Fabp5 KO (5KO), and Fabp7/Fabp5 double KO (7/5KO) mice and found that the number of NSCs/NPCs was dramatically reduced compared with wild-type mice. Although the uptake of BrdU 1 day after injection was decreased in all KO mice, the survival of BrdU+ cells 1 month after injection was increased in the 7/5KO mice compared to other three genotypes. We also observed an enhancement of neuronal differentiation in all Fabp KO mice. In addition, the proliferation and survival of NSCs/NPCs differed along the anterior-posterior axis (A-P axis). A greater number of newborn cells in the posterior region became extinct, but this tendency was not apparent in the Fabps KO mice. These data suggest that Fabp7 and Fabp5 have differential roles for proliferation and survival of the NSCs/NPCs during postnatal DG neurogenesis.
Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFAs) are essential nutrients. Dietary imbalance between these PUFAs, in particular high in n-6 PUFAs and low in n-3 PUFAs ...(n-6.sup.high/n-3.sup.low), is common in modern society. We have previously reported that C57BL/6 mouse male offspring derived from mothers exposed to an n-6.sup.high/n-3.sup.low diet during the gestation had an augmented ventral midbrain dopamine system in adulthood; however, the fatty acid composition in this brain region has not yet been investigated. This follow-up study aims to characterize the fatty acid profile of the ventral midbrain of mice exposed to the n-6.sup.high/n-3.sup.low diet during specific life stages. n-6 PUFAs, especially linoleic acid, were increased in the ventral midbrain of offspring exposed to the n-6.sup.high/n-3.sup.low diet during the gestation compared to those exposed to a well-balanced control diet throughout life. On the other hand, n-3 PUFAs, especially docosahexaenoic acid, were decreased in the ventral midbrain of offspring exposed to the n-6.sup.high/n-3.sup.low diet during the gestation, lactation, or postweaning period compared to those exposed to the control diet throughout life. Thus, exposure to the n-6.sup.high/n-3.sup.low diet in pregnancy increases linoleic acid and that in any life stage decreases docosahexaenoic acid in the offspring's ventral midbrain.
Docosahexaenoic acid (DHA; 22:6 ω-3) is highly enriched in the brain and is required for proper brain development and function. Its deficiency has been shown to be linked with the emergence of ...neurological diseases. Dietary ω-3 fatty acid supplements including DHA have been suggested to improve neuronal development and enhance cognitive functions. However, mechanisms of DHA incorporation in the brain remain to be fully understood. Findings suggested that DHA is better incorporated when esterified within lysophospholipid rather than under its non-esterified form. Furthermore, DHA has the potential to be converted into diverse oxylipins with potential neuroprotective effects. Since DHA is poorly synthesized de novo, targeting the brain with specific carriers of DHA might provide novel therapeutic approaches to neurodegenerative diseases.
•DHA and DHA-derived oxygenated metabolites provide neuroprotective effects.•Mfsd2a transporter is a major transporter of DHA to the brain.•LysoPC-DHA is preferentially transported through the blood-brain barrier.•AceDoPC is a stabilized form of LysoPC-DHA.•AceDoPC is also a preferential vector of DHA to the brain.
Background
During development, Cajal‐Retzius (CR) cells are the first generated and essential pioneering neurons that control neuronal migration and arealization in the mammalian cortex. CR cells are ...derived from specific regions within the telencephalon, that is, the pallial septum in the rostromedial cortex, the pallial‐subpallial boundary, and the cortical hem (CH) in the caudomedial cortex. However, the molecular mechanism underlying the generation of CR cell subtypes in distinct regions of origin is poorly understood.
Results
We found that double‐sex and mab‐3 related transcription factor (Dmrt) genes, that is, Dmrta1 and Dmrt3, were expressed in the progenitor domains that produce CR cells. The number of CH‐derived CR cells was severely decreased in Dmrt3 mutants, especially in Dmrta1 and Dmrt3 double mutants. The reduced production of the CR cells was consistent with the developmental impairment of the CH structures in the medial telencephalon from which the CR cells are produced.
Conclusion
Dmrta1 and Dmrt3 cooperatively regulate patterning of the CH structure and production of the CR cells from the CH during cortical development.
Key Findings
Dmrta1 and Dmrt3 (double‐sex and mab‐3 related transcription factor) are expressed in the progenitor domains that produce Cajal‐Retzius (CR) cells.
The number of CR cells, derived from the cortical hem (CH), is severely decreased in Dmrt3 mutants, especially in Dmrta1 and Dmrt3 double mutants.
The reduced production of the CR cells in Dmrt mutants is consistent with the developmental impairment of the CH structures from which the CR cells are produced.
Dietary intervention is a practical prevention strategy for age-related hearing loss (AHL). Omega-3 (n-3) polyunsaturated fatty acids (PUFAs) may be effective in prevention of AHL due to their ...anti-inflammatory and tissue-protective functions. Age-related changes in the hearing function of wild-type and Fat-1 transgenic mice derived from the C57BL/6N strain, which can convert omega-6 PUFAs to n-3 PUFAs and consequently produce enriched endogenous n-3 PUFAs, were investigated to test the efficacy of n-3 PUFAs for AHL prevention.
At 2 months, the baseline auditory brainstem response (ABR) thresholds were the same in Fat-1 and wild-type mice at 8-16 kHz but were significantly higher in Fat-1 mice at 4 and 32 kHz. In contrast, the ABR thresholds of Fat-1 mice were significantly lower at 10 months. Moreover, the ABR thresholds of Fat-1 mice at low-middle frequencies were significantly lower at 13 months (12 kHz). Body weights were significantly reduced in Fat-1 mice at 13 months, but not at 2, 10, and 16-17 months. In conclusion, enriched endogenous n-3 PUFAs produced due to the expression of the Fat-1 transgene partially alleviated AHL in male C57BL/6N mice.
The cerebellum regulates complex animal behaviors, such as motor control and spatial recognition, through communication with many other brain regions. The major targets of the cerebellar projections ...are the thalamic regions including the ventroanterior nucleus (VA) and ventrolateral nucleus (VL). Another thalamic target is the central lateral nucleus (CL), which receives the innervations mainly from the dentate nucleus (DN) in the cerebellum. Although previous electrophysiological studies suggest the role of the CL as the relay of cerebellar functions, the kinds of behavioral functions mediated by cerebellothalamic tracts projecting to the CL remain unknown. Here, we used immunotoxin (IT) targeting technology combined with a neuron-specific retrograde labeling technique, and selectively eliminated the cerebellothalamic tracts of mice. We confirmed that the number of neurons in the DN was selectively decreased by the IT treatment. These IT-treated mice showed normal overground locomotion with no ataxic behavior. However, elimination of these neurons impaired motor coordination in the rotarod test and forelimb movement in the reaching test. These mice showed intact acquisition and flexible change of spatial information processing in the place discrimination, Morris water maze, and T-maze tests. Although the tract labeling indicated the existence of axonal collaterals of the DN-CL pathway to the rostral part of the VA/VL complex, excitatory lesion of the rostral VA/VL did not show any significant alterations in motor coordination or forelimb reaching, suggesting no requirement of axonal branches connecting to the VL/VA complex for motor skill function. Taken together, our data highlight that the cerebellothalamic tracts projecting to the CL play a key role in the control of motor skills, including motor coordination and forelimb reaching, but not spatial recognition and its flexibility.
Omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFAs) are essential nutrients for normal brain development. The principal dietary n-6 and n-3 PUFAs are linoleic acid (LA) and ...α-linolenic acid (ALA), respectively, We have previously shown that maternal dietary imbalance between these PUFAs, i.e., rich in LA and poor in ALA, affected brain development and increased anxiety-related behavior in the mouse offspring. Here we further addressed sex difference in anxiety-related behavior in the offspring exposed to maternal LA:ALA imbalance. We fed pregnant mice a LA excess/ALA deficient (LAex/ALAdef) diet, and raised their offspring on a well-balanced LA:ALA diet from an early lactation period. When the offspring were grown to adulthood, they were subjected to behavioral and biochemical analyses. We found that both male and female offspring exposed to the LAex/ALAdef diet showed increased anxiety-related behavior compared to those exposed to the control diet, which was differently observed between the sexes. The female offspring also exhibited hyperactivity by maternal intake of the LAex/ALAdef diet. On the other hand, abnormal depressive behavior was undetected in both sexes. We also found that the ratio of n-6 to n-3 PUFAs in the brain was unaffected regardless of maternal diet or offspring’s sex. Since the n-6/n-3 ratio is known to influence emotional behavior, it is reasonable to assume that LA:ALA imbalance exposed during brain development is the key for causing enhanced anxiety in adulthood. The present study indicates that maternal dietary imbalance between LA and ALA increases offspring’s anxiety-related behavior with a sex-dependent manner.
► We evaluated Pax6 heterozygous neural stem cells by the neurosphere culture system. ► Proliferation was decreased after serial passages compared to the wild-type. ► Astrogenesis was promoted after ...serial passages compared to the wild-type. ► Pax6 is essential for the proliferation and differentiation of neural stem cells.
Neural stem/progenitor cells (NSPCs) are generated in early embryonic brains and maintained to produce neurons and glial cells in the central nervous system throughout the lifespan. A transcription factor Pax6 is a pivotal player in various neurodevelopmental processes. Previously, we have shown that Pax6 heterozygous rodents have defects in hippocampal neurogenesis and production of olfactory bulb interneurons. However, characters of NSPCs derived from Pax6 heterozygous rodents have not been studied in vitro. Here we examined the maintenance/proliferation and differentiation of Pax6 heterozygous mutant (rSey2/+) rat NSPCs in the neurosphere culture system. We found that the proliferative activity of NSPCs derived from rSey2/+ rats was reduced after serial passages. We also observed an excess astrogenesis in serially passaged NSPCs from rSey2/+ rats. These results show that Pax6 is essential for maintaining NSPCs and determining their differentiation fates.
Arachidonic acid (ARA) and docosahexaenoic acid (DHA), which are the dominant polyunsaturated fatty acids in the brain, have crucial roles in brain development and function. Recent studies have shown ...that ARA and DHA promote postnatal neurogenesis. However, the direct effects of ARA on neural stem/progenitor cells (NSPCs) and the effects of ARA and DHA on NSPCs at the neurogenic and subsequent gliogenic stages are still unknown. Here, we analyzed the effects of ARA and DHA on neurogenesis, specifically maintenance and differentiation, using neurosphere assays. We confirmed that primary neurospheres are neurogenic NSPCs and that tertiary neurospheres are gliogenic NSPCs. Regarding the effects of ARA and DHA on neurogenic NSPCs, ARA and DHA increased the number of neurospheres, whereas neither ARA nor DHA had a detectable effect on NSPCs in the differentiation condition. In gliogenic NSPCs, DHA increased the number of neurospheres, whereas ARA had no such effect. In contrast, ARA increased the number of astrocytes, whereas DHA increased the number of neurons in the differentiation condition. These results suggest that ARA promotes the maintenance of neurogenic NSPCs and might induce the glial differentiation of gliogenic NSPCs and that DHA promotes the maintenance of both neurogenic and gliogenic NSPCs and might lead to the neuronal differentiation of gliogenic NSPCs.
PDF
