Neurogenesis In Rats Research Articles

Can BDNF manipulate the overshoot-and-decline effect of adult neurogenesis during recovery from sleep deprivation?

Sleep deprivation reduces an organisms ability to perform adult neurogenesis, the generation of new neurons in adulthood. Recently, researchers discovered that recovery in sleep deprivation causes the rate of adult neurogenesis to overshoot the normal rate, and then decline back to normal. This research focuses on brain-derived neurotrophic factor, and whether or not manipulating it and its related pathways could extend the overshoot effect to enhance adult neurogenesis in the long term. The conclusion that is expected from this research is that BDNF will be able to prolong the overshoot of adult neurogenesis that is induced by sleep deprivation. The work seeks to provide more control over the overshoot-and-decline effect of adult neurogenesis during recovery from sleep deprivation, opening new pathways to treatments involving the manipulation of adult neurogenesis.

The influence of olfactory experience on the birthrates of olfactory sensory neurons with specific odorant receptor identities.

Olfactory sensory neurons (OSNs) are one of a few neuron types that are generated continuously throughout life in mammals. The persistence of olfactory sensory neurogenesis beyond early development has long been thought to function simply to replace neurons that are lost or damaged through exposure to environmental insults. The possibility that olfactory sensory neurogenesis may also serve an adaptive function has received relatively little consideration, largely due to the assumption that the generation of new OSNs is stochastic with respect to OSN subtype, as defined by the single odorant receptor gene that each neural precursor stochastically chooses for expression out of hundreds of possibilities. Accordingly, the relative birthrates of different OSN subtypes are predicted to be constant and impervious to olfactory experience. This assumption has been called into question, however, by evidence that the birthrates of specific OSN subtypes can be selectively altered by manipulating olfactory experience through olfactory deprivation, enrichment, and conditioning paradigms. Moreover, studies of recovery of the OSN population following injury provide further evidence that olfactory sensory neurogenesis may not be strictly stochastic with respect to subtype. Here we review this evidence and consider mechanistic and functional implications of the prospect that specific olfactory experiences can regulate olfactory sensory neurogenesis rates in a subtype-selective manner.

Embryonic origin of two ASD subtypes of social symptom severity: the larger the brain cortical organoid size, the more severe the social symptoms

BackgroundSocial affective and communication symptoms are central to autism spectrum disorder (ASD), yet their severity differs across toddlers: Some toddlers with ASD display improving abilities across early ages and develop good social and language skills, while others with “profound” autism have persistently low social, language and cognitive skills and require lifelong care. The biological origins of these opposite ASD social severity subtypes and developmental trajectories are not known.MethodsBecause ASD involves early brain overgrowth and excess neurons, we measured size and growth in 4910 embryonic-stage brain cortical organoids (BCOs) from a total of 10 toddlers with ASD and 6 controls (averaging 196 individual BCOs measured/subject). In a 2021 batch, we measured BCOs from 10 ASD and 5 controls. In a 2022 batch, we tested replicability of BCO size and growth effects by generating and measuring an independent batch of BCOs from 6 ASD and 4 control subjects. BCO size was analyzed within the context of our large, one-of-a-kind social symptom, social attention, social brain and social and language psychometric normative datasets ranging from N = 266 to N = 1902 toddlers. BCO growth rates were examined by measuring size changes between 1- and 2-months of organoid development. Neurogenesis markers at 2-months were examined at the cellular level. At the molecular level, we measured activity and expression of Ndel1; Ndel1 is a prime target for cell cycle-activated kinases; known to regulate cell cycle, proliferation, neurogenesis, and growth; and known to be involved in neuropsychiatric conditions.ResultsAt the BCO level, analyses showed BCO size was significantly enlarged by 39% and 41% in ASD in the 2021 and 2022 batches. The larger the embryonic BCO size, the more severe the ASD social symptoms. Correlations between BCO size and social symptoms were r = 0.719 in the 2021 batch and r = 0. 873 in the replication 2022 batch. ASD BCOs grew at an accelerated rate nearly 3 times faster than controls. At the cell level, the two largest ASD BCOs had accelerated neurogenesis. At the molecular level, Ndel1 activity was highly correlated with the growth rate and size of BCOs. Two BCO subtypes were found in ASD toddlers: Those in one subtype had very enlarged BCO size with accelerated rate of growth and neurogenesis; a profound autism clinical phenotype displaying severe social symptoms, reduced social attention, reduced cognitive, very low language and social IQ; and substantially altered growth in specific cortical social, language and sensory regions. Those in a second subtype had milder BCO enlargement and milder social, attention, cognitive, language and cortical differences.LimitationsLarger samples of ASD toddler-derived BCO and clinical phenotypes may reveal additional ASD embryonic subtypes.ConclusionsBy embryogenesis, the biological bases of two subtypes of ASD social and brain development—profound autism and mild autism—are already present and measurable and involve dysregulated cell proliferation and accelerated neurogenesis and growth. The larger the embryonic BCO size in ASD, the more severe the toddler’s social symptoms and the more reduced the social attention, language ability, and IQ, and the more atypical the growth of social and language brain regions.

Coffee polyphenols ameliorate early-life stress-induced cognitive deficits in male mice

Stress exposure during the sensitive period of early development has been shown to program the brain and increases the risk to develop cognitive deficits later in life. We have shown earlier that early-life stress (ES) leads to cognitive decline at an adult age, associated with changes in adult hippocampal neurogenesis and neuroinflammation. In particular, ES has been shown to affect neurogenesis rate and the survival of newborn cells later in life as well as microglia, modulating their response to immune or metabolic challenges later in life. Both of these processes possibly contribute to the ES-induced cognitive deficits. Emerging evidence by us and others indicates that early nutritional interventions can protect against these ES-induced effects through nutritional programming. Based on human metabolomics studies, we identified various coffee-related metabolites to be part of a protective molecular signature against cognitive decline in humans. Caffeic and chlorogenic acids are coffee-polyphenols and have been described to have potent anti-oxidant and anti-inflammatory actions. Therefore, we here aimed to test whether supplementing caffeic and chlorogenic acids to the early diet could also protect against ES-induced cognitive deficits. We induced ES via the limited nesting and bedding paradigm in mice from postnatal(P) day 2–9. On P2, mice received a diet to which 0.02% chlorogenic acid (5-O-caffeoylquinic acid) + 0.02% caffeic acid (3′,4′-dihydroxycinnamic acid) were added, or a control diet up until P42. At 4 months of age, all mice were subjected to a behavioral test battery and their brains were stained for markers for microglia and neurogenesis. We found that coffee polyphenols supplemented early in life protected against ES-induced cognitive deficits, potentially this is mediated by the survival of neurons or microglia, but possibly other mechanisms not studied here are mediating the effects. This study provides additional support for the potential of early nutritional interventions and highlights polyphenols as nutrients that can protect against cognitive decline, in particular for vulnerable populations exposed to ES.

Food for Thought: The Effects of Feeding on Neurogenesis in the Ball Python, Python regius

Introduction: Pythons are a well-studied model of postprandial physiological plasticity. Consuming a meal evokes a suite of physiological changes in pythons including one of the largest documented increases in post-feeding metabolic rates relative to resting values. However, little is known about how this plasticity manifests in the brain. Previous work has shown that cell proliferation in the python brain increases 6 days following meal consumption. This study aimed to confirm these findings and build on them in the long term by tracking the survival and maturation of these newly created cells across a 2-month period. Methods: We investigated differences in neural cell proliferation in ball pythons 6 days after a meal with immunofluorescence using the cell-birth marker 5-bromo-12′-deoxyuridine (BrdU). We investigated differences in neural cell maturation in ball pythons 2 months after a meal using double immunofluorescence for BrdU and a reptilian ortholog of the neuronal marker Fox3. Results: We did not find significantly greater rates of cell proliferation in snakes 6 days after feeding, but we did observe more new cells in neurogenic regions in fed snakes 2 months after the meal. Feeding was not associated with higher rates of neurogenesis, but snakes that received a meal had higher numbers of newly created nonneuronal cells than fasted controls. We documented particularly high cell survival rates in the olfactory bulbs and lateral cortex. Conclusion: Consuming a meal stimulates cell proliferation in the brains of ball pythons after digestion is complete, although this effect emerged at a later time point in this study than expected. Higher rates of proliferation partially account for greater numbers of newly created non-neuronal cells in the brains of fed snakes 2 months after the meal, but our results also suggest that feeding may have a mild neuroprotective effect. We captured a slight trend toward higher cell survival rates in fed snakes, and survival rates were particularly high in brain regions associated with olfactory perception and processing. These findings shed light on the relationship between energy balance and the creation of new neural cells in the brains of ball pythons.

Neonatal nociceptive stimulation results in pain sensitization, reduction of hippocampal 5-HT1A receptor, and p-CREB expression in adult female rats

Painful invasive procedures are often performed on newborns admitted to intensive care units (ICU). The acute and long-term effects caused by these stimuli can be investigated in animal models, such as newborn rats. Previous studies have shown that animals subjected to nociceptive stimuli in the neonatal period show sex-specific behavioral changes such as signs of anxiety or depression. Under the same conditions, neonatal stimuli also provoke an increase in the rate of neurogenesis and cell activation in the hippocampal dentate gyrus. So, this study aims to identify the possible roles of central monoamines, receptor expression (5-HT1A), and signaling factors (p-CREB) underlying the long-term effects of neonatal nociceptive stimulation. For this, noxious stimulation was induced by intra-plantar injection of Complete Freund´s adjuvant (CFA) on the postnatal day 1 (P1) or 8 (P8). Control animals were not stimulated. On P75 the behavioral tests were conducted (hotplate and elevated plus maze), followed by sacrifice and molecular studies. Our results showed that neonatal nociceptive stimulation alters pain sensitization specially in females, while stimulation on P1 increases pain threshold, P8-stimulated animals respond with reduced pain threshold (P < 0.001). Hippocampal expression of 5-HT1A receptor and p-CREB were reduced in P8 F group (P < 0.001) in opposition to the increased utilization rate of dopamine and serotonin in this group (P < 0.05). This study shows sex- and age-specific responses of signaling pathways within the hippocampus accompanied by altered behavioral repertoire, at long-term after neonatal painful stimulation.

Brain-Region-Specific Genes Form the Major Pathways Featuring Their Basic Functional Role: Their Implication in Animal Chronic Stress Model.

The analysis of RNA-Sec data from murine bulk tissue samples taken from five brain regions associated with behavior and stress response was conducted. The focus was on the most contrasting brain region-specific genes (BRSG) sets in terms of their expression rates. These BRSGs are identified as genes with a distinct outlying (high) expression rate in a specific region compared to others used in the study. The analysis suggested that BRSG sets form non-randomly connected compact gene networks, which correspond to the major neuron-mediated functional processes or pathways in each brain region. The number of BRSGs and the connection rate were found to depend on the heterogeneity and coordinated firing rate of neuron types in each brain region. The most connected pathways, along with the highest BRSG number, were observed in the Striatum, referred to as Medium Spiny Neurons (MSNs), which make up 95% of neurons and exhibit synchronous firing upon dopamine influx. However, the Ventral Tegmental Area/Medial Raphe Nucleus (VTA/MRN) regions, although primarily composed of monoaminergic neurons, do not fire synchronously, leading to a smaller BRSG number. The Hippocampus (HPC) region, on the other hand, displays significant neuronal heterogeneity, with glutamatergic neurons being the most numerous and synchronized. Interestingly, the two monoaminergic regions involved in the study displayed a common BRSG subnetwork architecture, emphasizing their proximity in terms of axonal throughput specifics and high-energy metabolism rates. This finding suggests the concerted evolution of monoaminergic neurons, leading to unique adaptations at the genic repertoire scale. With BRSG sets, we were able to highlight the contrasting features of the three groups: control, depressive, and aggressive mice in the animal chronic stress model. Specifically, we observed a decrease in serotonergic turnover in both the depressed and aggressive groups, while dopaminergic emission was high in both groups. There was also a notable absence of dopaminoceptive receptors on the postsynaptic membranes in the striatum in the depressed group. Additionally, we confirmed that neurogenesis BRSGs are specific to HPC, with the aggressive group showing attenuated neurogenesis rates compared to the control/depressive groups. We also confirmed that immune-competent cells like microglia and astrocytes play a crucial role in depressed phenotypes, including mitophagy-related gene Prkcd. Based on this analysis, we propose the use of BRSG sets as a suitable framework for evaluating case-control group-wise assessments of specific brain region gene pathway responses.

Tracking cell turnover in human brain using 15N-thymidine imaging mass spectrometry.

Microcephaly is often caused by an impairment of the generation of neurons in the brain, a process referred to as neurogenesis. While most neurogenesis in mammals occurs during brain development, it thought to continue to take place through adulthood in selected regions of the mammalian brain, notably the hippocampus. However, the generality of neurogenesis in the adult brain has been controversial. While studies in mice and rats have provided compelling evidence for neurogenesis occurring in the adult rodent hippocampus, the lack of applicability in humans of key methods to demonstrate neurogenesis has led to an intense debate about the existence and, in particular, the magnitude of neurogenesis in the adult human brain. Here, we demonstrate the applicability of a powerful method to address this debate, that is, the in vivo labeling of adult human patients with 15N-thymidine, a non-hazardous form of thymidine, an approach without any clinical harm or ethical concerns. 15N-thymidine incorporation into newly synthesized DNA of specific cells was quantified at the single-cell level with subcellular resolution by Multiple-isotype imaging mass spectrometry (MIMS) of brain tissue resected for medical reasons. Two adult human patients, a glioblastoma patient and a patient with drug-refractory right temporal lobe epilepsy, were infused for 24 h with 15N-thymidine. Detection of 15N-positive leukocyte nuclei in blood samples from these patients confirmed previous findings by others and demonstrated the appropriateness of this approach to search for the generation of new cells in the adult human brain. 15N-positive neural cells were easily identified in the glioblastoma tissue sample, and the range of the 15N signal suggested that cells that underwent S-phase fully or partially during the 24 h in vivo labeling period, as well as cells generated therefrom, were detected. In contrast, within the hippocampus tissue resected from the epilepsy patient, none of the 2,000 dentate gyrus neurons analyzed was positive for 15N-thymidine uptake, consistent with the notion that the rate of neurogenesis in the adult human hippocampus is rather low. Of note, the likelihood of detecting neurogenesis was reduced because of (i) the low number of cells analyzed, (ii) the fact that hippocampal tissue was explored that may have had reduced neurogenesis due to epilepsy, and (iii) the labeling period of 24 h which may have been too short to capture quiescent neural stem cells. Yet, overall, our approach to enrich NeuN-labeled neuronal nuclei by FACS prior to MIMS analysis provides a promising strategy to quantify even low rates of neurogenesis in the adult human hippocampus after in vivo15N-thymidine infusion. From a general point of view and regarding future perspectives, the in vivo labeling of humans with 15N-thymidine followed by MIMS analysis of brain tissue constitutes a novel approach to study mitotically active cells and their progeny in the brain, and thus allows a broad spectrum of studies of brain physiology and pathology, including microcephaly.

Spinal cord injury leads to more neurodegeneration in the hippocampus of aged male rats compared to young rats

Although the disruptive effects of spinal cord injury (SCI) on the hippocampus have been confirmed in some animal studies, no study has investigated its retrograde manifestations in the hippocampus of aged subjects. Herein, we compared the aged rats with young ones 3 weeks after the induction of SCI (Groups: Sham.Young, SCI.Young, Sham.Aged, SCI.Aged). The locomotion, hippocampal apoptosis, hippocampal rhythms (Delta, Theta, Beta, Gamma) max frequency (Max.rf) and power, hippocampal neurogenesis, and hippocampal receptors (NMDA, GABA A, Muscarinic1/M1), which are important in the generation of rhythms and neurogenesis, were compared in aged rats in contrast to young rats. At the end of the third week, the number of apoptotic (Tunel+) cells in the hippocampus (CA1, DG) of SCI animals was significantly higher compared to the sham animals, and also, it was significantly higher in the SCI.Aged group compared to SCI.Young group. Moreover, the rate of neurogenesis (DCX+, BrdU+ cells) and expression of M1 and NMDA receptors were significantly lower in the SCI.Aged group compared to SCI.Young group. The power and Max.fr of all rhythms were significantly lower in SCI groups compared to sham groups. Despite the decrease in the power of rhythms in the SCI.Aged group compared to SCI.Young group, there was no significant difference between them, and in terms of Max.fr index, only the Max.fr of theta and beta rhythms were significantly lower in the SCI.Aged group compared to SCI.Young group. This study showed that SCI could cause more neurodegeneration in the hippocampus of aged animals compared to young animals.

The atypical CDK activator RingoA/Spy1 regulates exit from quiescence in neural stem cells

In the adult mammalian brain, most neural stem cells (NSCs) are held in a reversible state of quiescence, which is essential to avoid NSC exhaustion and determine the appropriate neurogenesis rate. NSCs of the mouse adult subependymal niche provide neurons for olfactory circuits and can be found at different depths of quiescence, but very little is known on how their quiescence-to-activation transition is controlled. Here, we identify the atypical cyclin-dependent kinase (CDK) activator RingoA as a regulator of this process. We show that the expression of RingoA increases the levels of CDK activity and facilitates cell cycle entry of a subset of NSCs that divide slowly. Accordingly, RingoA-deficient mice exhibit reduced olfactory neurogenesis with an accumulation of quiescent NSCs. Our results indicate that RingoA plays an important role in setting the threshold of CDK activity required for adult NSCs to exit quiescence and may represent a dormancy regulator in adult mammalian tissues.

Stem Cell Treatments in Preclinical Relevant Stroke Models.

Since stroke has limited treatment options, an active search for new therapeutic approaches is required. Initial excitement of using cell-based therapies to stimulate recovery processes in the ischemic brain turned into a more measured perspective, acknowledging obstacles related to the unfavorable environments associated in part with aging. Given the predominance of stroke in older populations, evaluating the effectiveness of cell therapies in aged brain environments is essential and clinically relevant. Despite a common perception of the aged brain being resistant to regeneration, recent research with neural precursor cells and bone marrow-derived mesenchymal stem cells indicates that cell-based therapy can promote plasticity and remodeling in the aged rat brain. However, significant differences in the aged brain compared to the young brain, such as expedited progression of ischemic injury to brain infarction, decreased rate of endogenous neurogenesis, and delayed onset of neurological recovery, must be noted. The effectiveness of cell-based therapies may further be connected to age-related comorbidities such as diabetes or hyperlipidemia, potentially leading to maladaptive or impaired brain remodeling. These age-related factors need careful consideration in the clinical application of restorative therapies for stroke.

The rates of adult neurogenesis and oligodendrogenesis are linked to cell cycle regulation through p27-dependent gene repression of SOX2

Cell differentiation involves profound changes in global gene expression that often has to occur in coordination with cell cycle exit. Because cyclin-dependent kinase inhibitor p27 reportedly regulates proliferation of neural progenitor cells in the subependymal neurogenic niche of the adult mouse brain, but can also have effects on gene expression, we decided to molecularly analyze its role in adult neurogenesis and oligodendrogenesis. At the cell level, we show that p27 restricts residual cyclin-dependent kinase activity after mitogen withdrawal to antagonize cycling, but it is not essential for cell cycle exit. By integrating genome-wide gene expression and chromatin accessibility data, we find that p27 is coincidentally necessary to repress many genes involved in the transit from multipotentiality to differentiation, including those coding for neural progenitor transcription factors SOX2, OLIG2 and ASCL1. Our data reveal both a direct association of p27 with regulatory sequences in the three genes and an additional hierarchical relationship where p27 repression of Sox2 leads to reduced levels of its downstream targets Olig2 and Ascl1. In vivo, p27 is also required for the regulation of the proper level of SOX2 necessary for neuroblasts and oligodendroglial progenitor cells to timely exit cell cycle in a lineage-dependent manner.

Intermittent theta burst transcranial magnetic stimulation induces hippocampal mossy fibre plasticity in male but not female mice.

Transcranial magnetic stimulation (TMS) induces electric fields that depolarise or hyperpolarise neurons. Intermittent theta burst stimulation (iTBS), a patterned form of TMS that is delivered at the theta frequency (~5Hz), induces neuroplasticity in the hippocampus, a brain region that is implicated in memory and learning. One form of plasticity that is unique to the hippocampus is adult neurogenesis; however, little is known about whether TMS or iTBS in particular affects newborn neurons. Here, we therefore applied repeated sessions of iTBS to male and female mice and measured the extent of adult neurogenesis and the morphological features of immature neurons. We found that repeated sessions of iTBS did not significantly increase the amount of neurogenesis or affect the gross dendritic morphology of new neurons, and there were no sex differences in neurogenesis rates or aspects of afferent morphology. In contrast, efferent properties of newborn neurons varied as a function of sex and stimulation. Chronic iTBS increased the size of mossy fibre terminals, which synapse onto Cornu Ammonis 3 (CA3) pyramidal neurons, but only in males. iTBS also increased the number of terminal-associated filopodia, putative synapses onto inhibitory interneurons but only in male mice. This efferent plasticity could result from a general trophic effect, or it could reflect accelerated maturation of immature neurons. Given the important role of mossy fibre synapses in hippocampal learning, our results identify a neurobiological effect of iTBS that might be associated with sex-specific changes in cognition.

Modulatory Activity of the Endocannabinoid System in the Development and Proliferation of Cells in the CNS.

The Endocannabinoid System (ECS, also known as Endocannabinoidome) plays a key role in the function of the Central Nervous System, though the participation of this system on the early development - specifically in neuroprotection and proliferation of nerve cells - has been poorly studied. Here, we collect and describe evidence regarding how cannabinoid receptors CB1R and CB2R regulate several cell markers related to proliferation. While CB1R participates in the modulation of neuronal and glial proliferation, CB2R is involved in the proliferation of glial cells. The endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) exert significant effects on nerve cell proliferation. AEA generated during embryogenesis induces major effects on the differentiation of neuronal progenitor cells, whereas 2-AG participates in modulating cell migration events rather than affecting the neural proliferation rate. However, although the ECS has been demonstrated to participate in neuroprotection, more characterization on its role in neuronal and glial proliferation and differentiation is needed, especially in brain areas with recognized high neurogenesis rates. This has encouraged scientists to elucidate and propose specific mechanisms related with these cell proliferation mechanisms to better understand some neurodegenerative disorders such as Parkinson, Huntington and Alzheimer diseases, in which neuronal loss and poor neurogenesis are crucial factors for their onset and progression. In this review, we collect and present recent evidence published pointing to an active role of the ECS in the development and proliferation of nerve cells.

ODP269 Impacts of Gestational Bisphenol A Exposure on Adult Hypothalamic Neurogenesis

Abstract Regulation of physiological homeostasis by the hypothalamus is influenced by low basal levels of adult neurogenesis arising from proliferative cell populations in various hypothalamic regions. Adult hypothalamic neurogenesis is involved in maintenance of energy homeostasis and is responsive to energy balance disruptions. Hormones such as oestradiol interact with energy balance disruptions to alter rates of prenatal and adult neurogenesis, demonstrating sensitivity of hypothalamic neural progenitor cells to endogenous hormones. We previously showed that gestational exposure to the hormone mimic bisphenol A (BPA) accelerates embryonic hypothalamic neurogenesis with lasting effects on hypothalamic function into adulthood (1). The impact of gestational exposure to BPA on hypothalamic progenitors that contribute to adult neurogenesis has not been explored. The present study examines the interaction between energy balance disruptions via high-fat diet and the lasting impact of gestational BPA exposure on adult hypothalamic neurogenesis. Pregnant dams were either fed a control diet or chow laced with a low dose of BPA (50 μg per kg diet), then offspring were placed on low-fat or high-fat diet throughout adolescence (postnatal day (P) 5-35) and weighed every 5 days to assess physical changes. Intraperitoneal injections of BrdU were conducted twice a day from P45-53 to mark proliferating cells. To identify changes in the number and/or type of proliferating cells as a result of gestational BPA exposure and diet changes, brains from mice sacrificed at P54 and P75 were co-stained for BrdU and cell type specific markers to label neurons, oligodendrocytes, or astrocytes. Results showed that in adolescent animals on low-fat diet, BPA exposure decreased weight gain compared to controls (7.68±4.22 g vs. 8.50±3.98g;p&amp;lt; . 0001; n≥20 per group). Similarly, in adolescent animals on high-fat diet, BPA exposure decreased weight gain compared to controls (8.54±2. 02 g vs. 9.97±4.89g;p&amp;lt; . 0001; n≥20 per group). There was no impact on weight gain in adult male mice, however in adult female mice on low-fat diet, BPA exposure decreased weight gain compared to controls (18.33±1.45 g vs. 18.97±1.50 g;p=. 019; n≥7 per group). The opposite effect was seen in adult female mice on high-fat diet, where BPA exposure increased weight gain compared to controls (20. 07±1.51 g vs. 19.62±1.478 g;p=. 050; n≥7 per group). Preliminary data demonstrate a trending increase in hypothalamic neurogenesis in adult P54 females on low-fat diet exposed to BPA compared to controls (200.15±34.85 BrdU+/NeuN+ cells vs. 69. 00±6. 00 BrdU+/NeuN+ cells, n=2) and on high-fat diet exposed to BPA compared to controls (169.65±101.65 BrdU+/NeuN+ cells vs. 50.15±17.85 BrdU+/NeuN+ cells, n=2). These data suggest BPA may have an estrogenic effect on hypothalamic neural progenitors, resulting in disruptions to adult hypothalamic neurogenesis and energy balance homeostasis. Reference: (1) Nesan et al., Science Adv. 2021 May 28;7(22): eabd1159 . Presentation: No date and time listed

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.

Preconfigured dynamics in the hippocampus are guided by embryonic birthdate and rate of neurogenesis.

The incorporation of new information into the hippocampal network is likely to be constrained by its innate architecture and internally generated activity patterns. However, the origin, organization and consequences of such patterns remain poorly understood. In the present study we show that hippocampal network dynamics are affected by sequential neurogenesis. We birthdated CA1 pyramidal neurons with in utero electroporation over 4 embryonic days, encompassing the peak of hippocampal neurogenesis, and compared their functional features in freely moving adult mice. Neurons of the same birthdate displayed distinct connectivity, coactivity across brain states and assembly dynamics. Same-birthdate neurons exhibited overlapping spatial representations, which were maintained across different environments. Overall, the wiring and functional features of CA1 pyramidal neurons reflected a combination of birthdate and the rate of neurogenesis. These observations demonstrate that sequential neurogenesis during embryonic development shapes the preconfigured forms of adult network dynamics.

Chronic SSRI Treatment, but Not Norepinephrine Reuptake Inhibitor Treatment, Increases Neurogenesis in Juvenile Rats

There has been growing recognition that major depressive disorder is a serious medical disorder that also affects children. This has been accompanied by an increased use of antidepressant drugs in adolescents; however, not all classes of antidepressants are effective in children and adolescents. There is an increasing need to understand the differences in antidepressant action in different developmental stages. There are some data indicating that the behavioral effect of chronic antidepressant treatment in adult rodents is dependent on hippocampal neurogenesis; however, it is not known which classes of antidepressant drugs induce hippocampal neurogenesis in adolescent rodents. Three classes of antidepressant drugs were tested in two age groups of Sprague Dawley rats, pre-adolescent (postnatal days 11–24) and adolescent (postnatal days 21–34): monoamine oxidase inhibitors (MAOIs); selective serotonin reuptake inhibitors (SSRIs); serotonin norepinephrine reuptake inhibitors (SNRIs); and tricyclic antidepressants (TCAs). To address which classes of antidepressant drugs might alter the rate of mitogenesis in neural progenitor cells in an adolescent rodent model, adolescent Sprague Dawley rats were treated with the thymidine analog 5-bromo-deoxy-2′-uridine (BrdU) on postnatal days 21 and 22 and antidepressant drugs or vehicle for 14 days (postnatal days 21–34). To address which classes of antidepressant drugs might alter the rate of neurogenesis, postnatal day-21 Sprague Dawley rats were treated with antidepressant drugs or vehicle for 14 days (postnatal days 21–34) and BrdU on postnatal days 33 and 34. In both experimental paradigms, BrdU-positive cells in the subgranular zone and the granule cell layer were counted. Newborn neurons were identified in the neurogenic paradigm by identifying cells expressing both the neuronal specific marker NeuN and BrdU using confocal microscopy. Only the SSRI fluoxetine significantly altered the basal mitogenic and neurogenic rates in adolescent rats. Treatment with the monoamine oxidase inhibitor (MAOI) tranylcypromine (TCP) and the TCA desipramine did not alter the rate of hippocampal neurogenesis in the adolescent rats. This is consistent with human clinical observations, where only SSRIs have efficacy for treatment of depression in patients under the age of 18. In pre-adolescent rats, postnatal days 11–24, none of the drugs tested significantly altered the basal mitogenic or neurogenic rates. All of the classes of antidepressant drugs are known to induce hippocampal neurogenesis in adult rats. The mechanisms of action underlying this developmental difference in antidepressant drug action between juveniles and adults are not known.

Treatment with androgens plus estrogens cannot reverse sex differences in song and the song control nuclei in adult canaries

Adult treatments with testosterone (T) do not activate singing behavior nor promote growth of song control nuclei to the same extent in male and female canaries (Serinus canaria). Because T acts in part via aromatization into an estrogen and brain aromatase activity is lower in females than in males in many vertebrates, we hypothesized that this enzymatic difference might explain the sex differences seen even after exposure to the same amount of T. Three groups of castrated males and 3 groups of photoregressed females (i.e., with quiescent ovaries following exposure to short days) received either 2 empty 10 mm silastic implants, one empty implant and one implant filled with T or one implant filled with T plus one with estradiol (E2). Songs were recorded for 3 h each week for 6 weeks before brains were collected and song control nuclei volumes were measured in Nissl-stained sections. Multiple measures of song were still different in males and females following treatment with T. Co-administration of E2 did not improve these measures and even tended to inhibit some measures such as song rate and song duration. The volume of forebrain song control nuclei (HVC, RA, Area X) and the rate of neurogenesis in HVC was increased by the two steroid treatments, but remained significantly smaller in females than in males irrespective of the endocrine condition. These sex differences are thus not caused by a lower aromatization of the steroid; sex differences in canaries are probably organized either by early steroid action or by sex-specific gene regulation directly in the brain.

Systems genetics in the rat HXB/BXH family identifies Tti2 as a pleiotropic quantitative trait gene for adult hippocampal neurogenesis and serum glucose.

Neurogenesis in the adult hippocampus contributes to learning and memory in the healthy brain but is dysregulated in metabolic and neurodegenerative diseases. The molecular relationships between neural stem cell activity, adult neurogenesis, and global metabolism are largely unknown. Here we applied unbiased systems genetics methods to quantify genetic covariation among adult neurogenesis and metabolic phenotypes in peripheral tissues of a genetically diverse family of rat strains, derived from a cross between the spontaneously hypertensive (SHR/OlaIpcv) strain and Brown Norway (BN-Lx/Cub). The HXB/BXH family is a very well established model to dissect genetic variants that modulate metabolic and cardiovascular diseases and we have accumulated deep phenome and transcriptome data in a FAIR-compliant resource for systematic and integrative analyses. Here we measured rates of precursor cell proliferation, survival of new neurons, and gene expression in the hippocampus of the entire HXB/BXH family, including both parents. These data were combined with published metabolic phenotypes to detect a neurometabolic quantitative trait locus (QTL) for serum glucose and neuronal survival on Chromosome 16: 62.1-66.3 Mb. We subsequently fine-mapped the key phenotype to a locus that includes the Telo2-interacting protein 2 gene (Tti2)-a chaperone that modulates the activity and stability of PIKK kinases. To verify the hypothesis that differences in neurogenesis and glucose levels are caused by a polymorphism in Tti2, we generated a targeted frameshift mutation on the SHR/OlaIpcv background. Heterozygous SHR-Tti2+/- mutants had lower rates of hippocampal neurogenesis and hallmarks of dysglycemia compared to wild-type littermates. Our findings highlight Tti2 as a causal genetic link between glucose metabolism and structural brain plasticity. In humans, more than 800 genomic variants are linked to TTI2 expression, seven of which have associations to protein and blood stem cell factor concentrations, blood pressure and frontotemporal dementia.