Turmeric, and its active ingredient, curcumin, is one of nature's wonderful gifts. Not only is it the foundation for most curries (yum!), but it is also turning out to have impressive and far reaching health benefits, including:

• Acts as an anti-inflammatory pain killer
• Triggers apoptosis in cancer cells
• Inhibits the amyloid plaques that cause Alzheimer's Disease
• Enables the brain to generate new stem cells for neurons

This new research focuses on the last item in that list. If you choose to use a curcumin supplement, choose one that is standardized for 95% curcuminoids and also contains black pepper extract (piperine), which increases absorption of the curcumin considerably (as much as 2000% in one study) by inhibiting CYP3A4, an enzyme responsible for metabolism of drugs.

Let's start with a summary of the research from Science Daily:

Turmeric compound boosts regeneration of brain stem cells

Date: September 25, 2014
Source: BioMed Central

Summary:
A bioactive compound found in turmeric promotes stem cell proliferation and differentiation in the brain, reveals new research. The findings suggest aromatic turmerone could be a future drug candidate for treating neurological disorders, such as stroke and Alzheimer's disease.

A bioactive compound found in turmeric promotes stem cell proliferation and differentiation in the brain, reveals new research published today in the open access journal Stem Cell Research & Therapy. The findings suggest aromatic turmerone could be a future drug candidate for treating neurological disorders, such as stroke and Alzheimer's disease.

The study looked at the effects of aromatic (ar-) turmerone on endogenous neutral stem cells (NSC), which are stem cells found within adult brains. NSC differentiate into neurons, and play an important role in self-repair and recovery of brain function in neurodegenerative diseases. Previous studies of ar-turmerone have shown that the compound can block activation of microglia cells. When activated, these cells cause neuroinflammation, which is associated with different neurological disorders. However, ar-turmerone's impact on the brain's capacity to self-repair was unknown.

Researchers from the Institute of Neuroscience and Medicine in Jülich, Germany, studied the effects of ar-turmerone on NSC proliferation and differentiation both in vitro and in vivo. Rat fetal NSC were cultured and grown in six different concentrations of ar-turmerone over a 72 hour period. At certain concentrations, ar-turmerone was shown to increase NSC proliferation by up to 80%, without having any impact on cell death. The cell differentiation process also accelerated in ar-turmerone-treated cells compared to untreated control cells.

To test the effects of ar-turmerone on NSC in vivo, the researchers injected adult rats with ar-turmerone. Using PET imaging and a tracer to detect proliferating cells, they found that the subventricular zone (SVZ) was wider, and the hippocampus expanded, in the brains of rats injected with ar-turmerone than in control animals. The SVZ and hippocampus are the two sites in adult mammalian brains where neurogenesis, the growth of neurons, is known to occur.

Lead author of the study, Adele Rueger, said: "While several substances have been described to promote stem cell proliferation in the brain, fewer drugs additionally promote the differentiation of stem cells into neurons, which constitutes a major goal in regenerative medicine. Our findings on aromatic turmerone take us one step closer to achieving this goal."

Ar-turmerone is the lesser-studied of two major bioactive compounds found in turmeric. The other compound is curcumin, which is well known for its anti-inflammatory and neuroprotective properties.

Story Source:
The above story is based on materials provided by BioMed Central. Note: Materials may be edited for content and length.

Journal Reference:
Joerg Hucklenbroich, Rebecca Klein, Bernd Neumaier, Rudolf Graf, Gereon Fink, Michael Schroeter, Maria Rueger. (2014, Sep 26). Aromatic-turmerone induces neural stem cell proliferation in vitro and in vivo. Stem Cell Research & Therapy; 5(4): 100 DOI: 10.1186/scrt500

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Here is the beginning of the article, including the abstract and the introduction. The article is open access.

Aromatic-turmerone induces neural stem cell proliferation in vitro and in vivo

Joerg Hucklenbroich [1,2], Rebecca Klein [2,3], Bernd Neumaier [3], Rudolf Graf [3], Gereon Rudolf Fink [1,2], Michael Schroeter [1,2,3] and Maria Adele Rueger [1,2,3]

1, Cognitive Neuroscience, Institute of Neuroscience and Medicine (INM-3), Research Centre Juelich, Leo-Brandt-Straße 52425, Jülich, Germany
2. Department of Neurology, University Hospital of Cologne, Cologne, Germany
3. Max Planck Institute for Neurological Research, Cologne, Germany

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Stem Cell Research & Therapy 2014, 5(4):100 doi:10.1186/scrt500 

Abstract

Introduction

Aromatic (ar-) turmerone is a major bioactive compound of the herb Curcuma longa. It has been suggested that ar-turmerone inhibits microglia activation, a property that may be useful in treating neurodegenerative disease. Furthermore, the effects of ar-turmerone on neural stem cells (NSCs) remain to be investigated.

Methods

We exposed primary fetal rat NSCs to various concentrations of ar-turmerone. Thereafter, cell proliferation and differentiation potential were assessed. In vivo, naïve rats were treated with a single intracerebroventricular (i.c.v.) injection of ar-turmerone. Proliferative activity of endogenous NSCs was assessed in vivo, by using noninvasive positron emission tomography (PET) imaging and the tracer [18F]-fluoro-L-thymidine ([18F]FLT), as well as ex vivo.

Results

In vitro, ar-turmerone increased dose-dependently the number of cultured NSCs, because of an increase in NSC proliferation (P < 0.01). Proliferation data were supported by qPCR-data for Ki-67 mRNA. In vitro as well as in vivo, ar-turmerone promoted neuronal differentiation of NSCs. In vivo, after i.c.v. injection of ar-turmerone, proliferating NSCs were mobilized from the subventricular zone (SVZ) and the hippocampus of adult rats, as demonstrated by both [18F]FLT-PET and histology (P < 0.05).

Conclusions

Both in vitro and in vivo data suggest that ar-turmerone induces NSC proliferation. Ar-turmerone thus constitutes a promising candidate to support regeneration in neurologic disease.
 

Introduction

Curcumin and ar-turmerone are the major bioactive compounds of the herb Curcuma longa. Although many studies have demonstrated curcumin to possess antiinflammatory and neuroprotective properties (reviewed by [1]), to date, the effects of ar-turmerone remain to be elucidated. For example, antitumor properties, exerted via the induction of apoptosis [2] and inhibition of tumor cell invasion [3], have been attributed to ar-turmerone. Park et al. [4,5] recently suggested that ar-turmerone also possesses antiinflammatory properties resulting from the blockade of key signaling pathways in microglia. Because microglia activation is a hallmark of neuroinflammation and is associated with various neurologic disorders, including neurodegenerative diseases [6,7] and stroke [8,9], ar-turmerone constitutes a promising therapeutic agent for various neurologic disorders.

The regenerative potential of endogenous neural stem cells (NSCs) plays an important role in neurodegenerative disease and stroke. Endogenous NSCs are mobilized by cerebral ischemia [10] as well as by various neurodegenerative diseases [11,12], although their intrinsic regenerative response is insufficient to enable functional recovery. The targeted (that is, pharmacologic) activation of endogenous NSCs has been shown to enhance self-repair and recovery of function in the adult brain in both stroke [13,14] and neurodegeneration [15]. Importantly, NSCs and microglia relevantly interact with each other, thereby affecting their respective functions [16,17].

Thus, with the perspective of ar-turmerone as a therapeutic option in mind, we investigated the effects of ar-turmerone on NSCs in vitro and in vivo.

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Here is a collection of articles complied by Examiner.com on their page on curcumin. Some of these studies show that curcumin is not effective for certain conditions. For a short-cut to seeing where curcumin is effective, the Examiner page has a handy little chart - The Human Effect Matrix.

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Interesting new research out of Duke University on how specific neurons tell neuronal stem cells where to go to repair damage. Below this press release is the abstract and citation from Nature Neuroscience (where the article is, of course, embargoed).

Neuron Tells Stem Cells to Grow New Neurons

Researchers identify first piece of new brain-repair circuit

June 2, 2014 | By Karl Leif Bates

In this artist's representation of the adult subependymal neurogenic niche (viewed from underneath the ependyma), electrical signals generated by the ChAT+ neuron give rise to newborn migrating neuroblasts, seen moving over the underside of ependymal cells. Illustration by O’Reilly Science Art.

Durham, NC - Duke researchers have found a new type of neuron in the adult brain that is capable of telling stem cells to make more new neurons. Though the experiments are in their early stages, the finding opens the tantalizing possibility that the brain may be able to repair itself from within.

Neuroscientists have suspected for some time that the brain has some capacity to direct the manufacturing of new neurons, but it was difficult to determine where these instructions are coming from, explains Chay Kuo, M.D. Ph.D., an assistant professor of cell biology, neurobiology and pediatrics.

In a study with mice, his team found a previously unknown population of neurons within the subventricular zone (SVZ) neurogenic niche of the adult brain, adjacent to the striatum. These neurons expressed the choline acetyltransferase (ChAT) enzyme, which is required to make the neurotransmitter acetylcholine. With optogenetic tools that allowed the team to tune the firing frequency of these ChAT+ neurons up and down with laser light, they were able to see clear changes in neural stem cell proliferation in the brain.

The findings appeared as an advance online publication June 1 in the journal Nature Neuroscience.

The mature ChAT+ neuron population is just one part of an undescribed neural circuit that apparently talks to stem cells and tells them to increase new neuron production, Kuo said. Researchers don't know all the parts of the circuit yet, nor the code it's using, but by controlling ChAT+ neurons' signals Kuo and his Duke colleagues have established that these neurons are necessary and sufficient to control the production of new neurons from the SVZ niche.

"We have been working to determine how neurogenesis is sustained in the adult brain. It is very unexpected and exciting to uncover this hidden gateway, a neural circuit that can directly instruct the stem cells to make more immature neurons," said Kuo, who is also the George W. Brumley, Jr. M.D. assistant professor of developmental biology and a member of the Duke Institute for Brain Sciences. "It has been this fascinating treasure hunt that appeared to dead-end on multiple occasions!"

Kuo said this project was initiated more than five years ago when lead author Patricia Paez-Gonzalez, a postdoctoral fellow, came across neuronal processes contacting neural stem cells while studying how the SVZ niche was assembled.

The young neurons produced by these signals were destined for the olfactory bulb in rodents, as the mouse has a large amount of its brain devoted to process the sense of smell and needs these new neurons to support learning. But in humans, with a much less impressive olfactory bulb, Kuo said it's possible new neurons are produced for other brain regions. One such region may be the striatum, which mediates motor and cognitive controls between the cortex and the complex basal ganglia.

"The brain gives up prime real estate around the lateral ventricles for the SVZ niche housing these stem cells," Kuo said. "Is it some kind of factory taking orders?" Postdoctoral fellow Brent Asrican made a key observation that orders from the novel ChAT+ neurons were heard clearly by SVZ stem cells.

Studies of stroke injury in rodents have noted SVZ cells apparently migrating into the neighboring striatum. And just last month in the journal Cell, a Swedish team observed newly made control neurons called interneurons in the human striatum for the first time. They reported that interestingly in Huntington's disease patients, this area seems to lack the newborn interneurons.

"This is a very important and relevant cell population that is controlling those stem cells," said Sally Temple, director of the Neural Stem Cell Institute of Rensselaer, NY, who was not involved in this research. "It's really interesting to see how innervations are coming into play now in the subventricular zone."

Kuo's team found this system by following cholinergic signaling, but other groups are arriving in the same niche by following dopaminergic and serotonergic signals, Temple said. "It's a really hot area because it's a beautiful stem cell niche to study. It's this gorgeous niche where you can observe cell-to-cell interactions."

These emerging threads have Kuo hopeful researchers will eventually be able to find the way to "engage certain circuits of the brain to lead to a hardware upgrade. Wouldn't it be nice if you could upgrade the brain hardware to keep up with the new software?" He said perhaps there will be a way to combine behavioral therapy and stem cell treatments after a brain injury to rebuild some of the damage.

The questions ahead are both upstream from the new ChAT+ neurons and downstream, Kuo says. Upstream, what brain signals tell ChAT+ neurons to start asking the stem cells for more young neurons? Downstream, what's the logic governing the response of the stem cells to different frequencies of ChAT+ electrical activity?

There's also the big issue of somehow being able to introduce new components into an existing neuronal circuit, a practice that parts of the brain might normally resist. "I think that some neural circuits welcome new members, and some don't," Kuo said.

In addition to Paez-Gonzalez, Asrican, and Kuo, Erica Rodriguez, a graduate student in the neurobiology training program, is also an author. This research was supported by the National Institutes of Health, David & Lucile Packard Foundation, and George Brumley Jr. Endowment.

More Information
Contact: Karl Leif Bates
Phone: (919) 681-8054
Email: karl.bates@duke.edu © 2014 Office of News & Communications
615 Chapel Drive, Box 90563, Durham, NC 27708-0563 | (919) 684-2823

* * * * *

Full Citation:
Paez-Gonzalez, P, Asrican, B, Rodriguez, E, and Kuo, CT, (2014, June 1). Identification of distinct ChAT+ neurons and activity-dependent control of postnatal SVZ neurogenesis. Nature Neuroscience; doi:10.1038/nn.3734 - ePub ahead of print

Identification of distinct ChAT+ neurons and activity-dependent control of postnatal SVZ neurogenesis

Patricia Paez-Gonzalez, Brent Asrican, Erica Rodriguez & Chay T Kuo

Abstract

Postnatal and adult subventricular zone (SVZ) neurogenesis is believed to be primarily controlled by neural stem cell (NSC)-intrinsic mechanisms, interacting with extracellular and niche-driven cues. Although behavioral experiments and disease states have suggested possibilities for higher level inputs, it is unknown whether neural activity patterns from discrete circuits can directly regulate SVZ neurogenesis. We identified a previously unknown population of choline acetyltransferase (ChAT)+ neurons residing in the rodent SVZ neurogenic niche. These neurons showed morphological and functional differences from neighboring striatal counterparts and released acetylcholine locally in an activity-dependent fashion. Optogenetic inhibition and stimulation of subependymal ChAT+ neurons in vivo indicated that they were necessary and sufficient to control neurogenic proliferation. Furthermore, whole-cell recordings and biochemical experiments revealed direct SVZ NSC responses to local acetylcholine release, synergizing with fibroblast growth factor receptor activation to increase neuroblast production. These results reveal an unknown gateway connecting SVZ neurogenesis to neuronal activity-dependent control and suggest possibilities for modulating neuroregenerative capacities in health and disease.

Two Articles on Hippocampal Neurogenesis

 

The first of these two articles looks at the history and current state of our knowledge of neurogenesis in the adult hippocampus. The second article reveals research suggesting the social isolation inhibits hippocampal neurogenesis.

From Wikipedia:

Neurogenesis (birth of neurons) is the process by which neurons are generated from neural stem cells and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of mammals: the hippocampus and the subventricular zone. Studies have indicated that the hormone testosterone in vertebrates, and the prohormone ecdysone in insects, have an influence on the rate of neurogenesis.

The first article is a briefer review piece, so it is included here in its entirety. The second article is much longer and only the abstract and introduction are included.

Functional neurogenesis in the adult hippocampus: Then and now

Krishna C. Vadodaria [1,2] and Sebastian Jessberger [1,2]

1. Faculty of Medicine and Science, Brain Research Institute, University of Zurich, Zurich, Switzerland
2. Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland
Introduction

After two decades of research, the neurosciences have come a long way from accepting that neural stem/progenitor cells (NSPCs) generate new neurons in the adult mammalian hippocampus to unraveling the functional role of adult-born neurons in cognition and emotional control. The finding that new neurons are born and become integrated into a mature circuitry throughout life has challenged and subsequently reshaped our understanding of neural plasticity in the adult mammalian brain. It is now widely accepted that neurogenesis in the adult central nervous system occurs in multiple brain regions within the rodent brain, including the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) of the dentate gyrus (DG). Since the discovery of ongoing neurogenesis in the adult brain, the field has been addressing questions regarding the cellular identity of adult NSPCs, the molecular pathways regulating maturation and integration of newborn neurons into preexisting circuitries, and how new neurons contribute to adult brain function. Technological advances over the last two decades such as targeted modulation (loss- and gain-of-function) of adult neurogenesis and refinements in behavioral testing paradigms have enabled us to begin addressing these questions directly. Here we give a brief overview of old and new studies examining the function of adult hippocampal neurogenesis (AHN) in the context of evolving technology, which has exponentially expanded our understanding of the neurogenic process in the adult mammalian brain.

Early Studies: From Correlation to Causality

Early on, the field went through a phase of correlating levels of AHN with performance in behavioral tests of hippocampus-dependent learning and memory, and affective behavior. Manipulations that increase AHN such as environmental enrichment, physical activity, and also treatment with certain antidepressants were found to enhance performance in spatial navigation tasks (e.g., Morris water maze; MWM) and in tests of anxiety-related behaviors (forced swim test, elevated plus maze) (Kim et al., 2012). Conversely, stress, aging, and inflammation, all of which negatively affect AHN, resulted in decreased performance in tasks of spatial navigation and emotion-related behaviors (Kim et al., 2012). Although correlative, these data generated in the late 1990s and early 2000s, suggested a role for AHN in hippocampus-dependent processes of cognition and emotion. The first studies attempting to show causal relationship between AHN and hippocampus-dependent behavior were published in the early 2000s, using the antimitotic drug methylazoxymethanol acetate (MAM) and focal irradiation of the hippocampus to ablate AHN. MAM-treated and focally irradiated mice showed impairments in hippocampus-dependent trace-conditioning and certain forms of long-term spatial memory (Shors et al., 2001; Snyder et al., 2005; Deng et al., 2009), suggesting that AHN was required for particular aspects of learning and memory. However, seemingly inconsistent findings from multiple studies with confounding variables such as incomplete elimination of neurogenesis and unwanted off-target effects (such as irradiation-induced inflammation) impeded a precise understanding of the contribution of AHN to hippocampal function (Deng et al., 2010).

Functional Hippocampal Neurogenesis and Evolving Methodology

Significant advances in conditional gene targeting allowing the generation of transgenic mice and virus-based approaches enabled the selective targeting of adult hippocampal NSPCs and their neuronal progeny, and revealed not only the molecular pathways important for the different stages of neurogenesis, but also specific behavioral correlates of altered AHN (Saxe et al., 2006; Dupret et al., 2008; Jessberger et al., 2009; Deng et al., 2010; Ming and Song, 2011). Commonly used approaches include the expression of cell death-inducing genes (such as diphtheria toxin or its receptor and thymidine kinase that kills dividing cells upon gancyclovir injections), overexpression of pro-apoptotic genes (such as Bax), and expression of light-sensitive ion channels (such as channelrhodopsins enabling conditional depolarization or hyperpolarization of newborn neurons) in NSPCs and/or their neuronal progeny (Deng et al., 2010). Fewer methods have been utilized to genetically boost neurogenesis. One elegant approach has been to utilize transgenic mice where the pro-apoptotic gene BAX was conditionally deleted in nestin-expressing NSPCs (iBAXnestin), resulting in substantially enhanced levels of AHN (Sahay et al., 2011a). As compared to previous cytostatic drug- and irradiation-based strategies, these techniques improved temporal and tissue-specific control for ablating the desired neuronal population. Studies utilizing these strategies in combination with an array of behavioral tests have revealed novel roles for AHN. Together with correlational studies, genetic, and pharmacological approaches to manipulate levels of AHN are currently being used to understand the functional significance of AHN. Spatial discrimination tasks such as feared context, radial-arm maze, modified MWM, and the two-choice discrimination task have been utilized to test for a function of newborn neurons (Saxe et al., 2007; Clelland et al., 2009; Deng et al., 2009; Sahay et al., 2011a; Nakashiba et al., 2012) and there is now sufficient evidence suggesting that AHN plays a crucial role in the pattern separation functions of the DG (Treves et al., 2008; Yassa and Stark, 2011). The two-choice discrimination task where mice must discriminate between spatially proximate stimuli may become one of the behavioral tasks of choice (Clelland et al., 2009; Mctighe et al., 2009). Complementary approaches to knockdown AHN revealed selective deficits in this task and the radial arm maze. On the other hand, boosting AHN by genetically enhancing newborn neuron survival (using iBaxnestin) enhances discrimination between similar contexts in a contextual fear-conditioning task (Sahay et al., 2011a). Notably, AHN becomes critical only when contexts/patterns become more similar and therefore more difficult to discriminate during recall; thus, AHN seems to be dispensable for discriminating between highly dissimilar contexts/patterns but crucial for computing and discerning highly similar input patterns. Transgenic strategies enabling selective ablation of young and adult-born DG neurons vs. mature DG granule neurons in combination with modifications of the MWM show that in the absence of mature neurons, separation between similar spatial contexts is enhanced, whereas, “completing” a pattern with only a subset of the cues is impaired (Nakashiba et al., 2012). These results highlight an interesting interplay between “newborn” and “old” neuronal populations, suggesting different yet complementary functions of pattern “separation” vs. “completion,” respectively. Collectively, studies from multiple labs provide evidence of a strong link between AHN and proposed pattern separation functions of the DG (Sahay et al., 2011b). Furthermore, recent data using novel transgenic mice and virus-based approaches (e.g., optogenetics and TK-based approaches) support the hypothesis that new neurons are particularly important for memory encoding and retrieval during a critical period 4–8 weeks after new neurons are born (Deng et al., 2009; Gu et al., 2012).

Recent reports also support a role for AHN in emotional control and affective behavior. These studies benefitted not only from novel methods to ablate AHN, but also refinements in testing paradigms for specific aspects of emotion-related behaviors (Samuels and Hen, 2011; Kheirbek et al., 2012). Particularly, irradiated and transgenic mice with diminished AHN exhibit signs of heightened stress response as observed in the food avoidance test (after acute stress), increased despair-like behavior in the forced swim test, and increased anhedonia in sucrose preference tests (Snyder et al., 2011). These deficits may be in part due to a dysfunctional regulation of the hypothalamic-pituitary-adrenal (HPA) axis that may lead to a disproportionate response to stress-inducing stimuli in mice with impaired AHN (Snyder et al., 2011). Interestingly, although ablation of AHN led to a heightened stress response along with behavioral correlates of depression-like behaviors, increasing neurogenesis by itself does not appear to be sufficient for promoting anxiolytic or antidepressant-like behaviors in the iBax mice (Sahay et al., 2011a). However, this may be due to a “ceiling” effect or due to limitations of current testing paradigms for examining “gain of function” in emotion-related behaviors.
 

Functional AHN: Open Questions

Accumulating evidence over the last years has clearly demonstrated a role for AHN in hippocampus-dependent cognition and emotional control. However, it is currently unclear how exactly newborn neurons shape the DG circuitry and mediate DG-dependent pattern separation. A large number of open questions remain: how are individual patterns represented in the DG (Deng et al., 2013)? How does the hippocampal circuit “change” with the addition of each pattern-associated cohort of newborn neurons? How does top-down or cortical input regulate AHN and its function in learning new information? How much do newborn young neurons contribute to memory engrams in the DG? How do adult-born hippocampal neurons regulate the HPA axis, which contributes to the neurogenesis-associated regulation of anxiety-related behaviors? Do distinct subsets of newborn neurons contribute to pattern separation vs. emotional regulation role of the DG? Other questions pertain to the relevance of varying levels of AHN, basally, by environmental stimuli, and in the context of disease: How do variations in AHN contribute to individuality in exploratory behavior and could this be extended to humans (Freund et al., 2013)? How does aging regulate AHN and can boosting AHN alleviate age-related decline in aspects of cognition? Can AHN be harnessed for endogenous brain repair and restoration of neuronal function in diseases that is associated with diminished or altered AHN, such as major depression, epilepsy, Alzheimer's disease, and Parkinson's disease? Interestingly, recent findings that levels of hippocampal neurogenesis remain substantial even through the fifth decade of life in the adult human brain, opens up possibilities for doing functional studies in humans related to AHN (Spalding et al., 2013), for example by combining non-invasive imaging strategies together with DG-dependent behavioral paradigms (Brickman et al., 2011; Yassa and Stark, 2011; Dery et al., 2013). With the development of novel genetic tools there is great hope for answering these questions, however, it also seems plausible that we need to develop more refined and sensitive testing paradigms to closely examine AHN-dependent behaviors. In addition, it is clear that most genetic approaches are only suitable for studies using mice, limiting the possibility to use different species to broaden the relevance of the obtained findings. Thus, developing novel methods to measure and /or manipulate AHN in primates and even humans will be important to move the field toward biomedical relevance.

Be that as it may, the finding that the adult mammalian brain continuously generates new neurons throughout life has contributed significantly to our understanding of brain functioning and recent technological advances provide further impetus for studying the function of AHN in health and disease.

Acknowledgments

Krishna C. Vadodaria is currently supported by a postdoctoral fellowship of the Swiss National Science Foundation (SNSF). We apologize to all authors whose work is not cited due to space constraints.
 
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Social isolation disrupts hippocampal neurogenesis in young non-human primates

Simone M. Cinini [1], Gabriela F. Barnabe [1], Nicole Galvão-Coelho [2], Magda A. de Medeiros [3], Patrícia Perez-Mendes [1], Maria B. C. Sousa [2], Luciene Covolan [1] and Luiz E. Mello [1]

1. Departamento de Fisiologia, Universidade Federal de São Paulo, São Paulo, Brazil
2. Departamento de Fisiologia, Universidade Federal do Rio Grande do Norte, Natal, Brazil
3. Departamento de Ciências Fisiológicas, Universidade Federal Rural do Rio de Janeiro, Seropédica, Rio de Janeiro Brazil

Social relationships are crucial for the development and maintenance of normal behavior in non-human primates. Animals that are raised in isolation develop abnormal patterns of behavior that persist even when they are later reunited with their parents. In rodents, social isolation is a stressful event and is associated with a decrease in hippocampal neurogenesis but considerably less is known about the effects of social isolation in non-human primates during the transition from adolescence to adulthood. To investigate how social isolation affects young marmosets, these were isolated from other members of the colony for 1 or 3 weeks and evaluated for alterations in their behavior and hippocampal cell proliferation. We found that anxiety-related behaviors like scent-marking and locomotor activity increased after social isolation when compared to baseline levels. In agreement, grooming—an indicative of attenuation of tension—was reduced among isolated marmosets. These results were consistent with increased cortisol levels after 1 and 3 weeks of isolation. After social isolation (1 or 3 weeks), reduced proliferation of neural cells in the subgranular zone of dentate granule cell layer was identified and a smaller proportion of BrdU-positive cells underwent neuronal fate (doublecortin labeling). Our data is consistent with the notion that social deprivation during the transition from adolescence to adulthood leads to stress and produces anxiety-like behaviors that in turn might affect neurogenesis and contribute to the deleterious consequences of prolonged stressful conditions.

Introduction

In the adult hippocampus, progenitor cells in the subgranular zone of the dentate gyrus give rise to new neurons that migrate into the granule cell layer, differentiate into granular neurons, and are capable of functional integration into the hippocampal circuitry (Gould and Gross, 2002; Van Praag et al., 2002; Kee et al., 2007). The functional role of hippocampal neurogenesis has not been fully understood until now, but despite the divergent results from different laboratories and models, most data points toward its involvement with specific aspects of learning, conditioning, and spatial information (for review see Balu and Lucki, 2009).

Reduction in hippocampal neurogenesis is associated with stress (Gould et al., 1998) mainly by means of increased excitatory transmission (Gould et al., 1997; Abraham et al., 1998), pro-inflammatory cytokines (Koo and Duman, 2008), diminished neurotrophins expression (Duman and Monteggia, 2006; Jacobsen and Mork, 2006), and glucocorticoid signaling (Wong and Herbert, 2005, 2006). Social isolation is a form of stress, which affects some hippocampal-related functions such as learning and memory and may lead to affective disorders. In marmosets there is a strong exponential negative correlation between the number of dentate proliferating cells and aging where 2–3 years-old animals are considered young adults, from 4 to 7 years they are middle-aged and above 8 years old they are considered old (Bunk et al., 2011). In the present study we used social isolation of young animals as the stressful event (Laudenslager et al., 1995; Stranahan et al., 2006) in order to characterize behavioral consequences of social isolation during the transition phase from adolescence to adulthood, when the animals are at the peak of dentate neurogenesis, so any disturbance might bear a greater relevance in the onset of future mood disorders.

The long-term effects of social isolation among rodent pups include decreased hippocampal neurogenesis, which can culminate in a reduced ability to cope with stressful events in adulthood (Laudenslager et al., 1995; Mirescu et al., 2004; Karten et al., 2005; Stranahan et al., 2006; Rizzi et al., 2007). As compared to rodents, social interactions in primates are considerably more important for the appropriate neuropsychological development (Rosenblum and Andrews, 1994). Marmosets partially deprived of parental care during infancy develop abnormal patterns of behavior that persist even when they are later reunited with their parents (Dettling et al., 2002a,b). In spite of the well-characterized behavioral consequences of social isolation during infancy in these animals, little is known about the neurobiological effects of social isolation during its transition to adulthood. In the present study we investigate the consequences of social isolation in the behavior and hippocampal neurogenesis in these non-human primates.

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