Running throughout Middle-Age Keeps Old Adult-Born Neurons Wired.

Exercise may prevent or delay aging-related memory loss and neurodegeneration. In rodents, running increases the number of adult-born neurons in the dentate gyrus (DG) of the hippocampus, in association with improved synaptic plasticity and memory function. However, it is unclear whether adult-born neurons remain fully integrated into the hippocampal network during aging and whether long-term running affects their connectivity. To address this issue, we labeled proliferating DG neural progenitor cells with retrovirus expressing the avian TVA receptor in two-month-old sedentary and running male C57Bl/6 mice. More than six months later, we injected EnvA-pseudotyped rabies virus into the DG as a monosynaptic retrograde tracer, to selectively infect TVA expressing "old" new neurons. We identified and quantified the direct afferent inputs to these adult-born neurons within the hippocampus and (sub)cortical areas. Here, we show that long-term running substantially modifies the network of the neurons generated in young adult mice, upon middle-age. Exercise increases input from hippocampal interneurons onto "old" adult-born neurons, which may play a role in reducing aging-related hippocampal hyperexcitability. In addition, running prevents the loss of adult-born neuron innervation from perirhinal cortex, and increases input from subiculum and entorhinal cortex, brain areas that are essential for contextual and spatial memory. Thus, long-term running maintains the wiring of "old" new neurons, born during early adulthood, within a network that is important for memory function during aging.

Long-term taurine administration improves motor skills in a tubulinopathy rat model by decreasing oxidative stress and promoting myelination.

The taiep rat undergoes hypomyelination and progressive demyelination caused by an abnormal microtubule accumulation in oligodendrocytes, which elicits neuroinflammation and motor behavior dysfunction. Based on taurine antioxidant and proliferative actions, this work explored whether its sustained administration from the embryonic age to adulthood could prevent neuroinflammation, stimulate cell proliferation, promote myelination, and relieve motor impairment. Taurine (50 mg/L of drinking water = 50 ppm) was given to taiep pregnant rats on gestational day 15 and afterward to the male offspring until eight months of age. We measured the levels of nitric oxide (NO), malondialdehyde + 4-hydroxyalkenals (MDA + 4-HDA), CXCL1, CXCR2 receptor, growth factors (BNDF and FGF2), cell proliferation, and myelin content over time. Integral motor behavior was also evaluated. Our results showed that taurine administration significantly decreased NO and MDA + 4-HDA levels, increased cell proliferation, and promoted myelination in an age- and brain region-dependent fashion compared with untreated taiep rats. Taurine effect on chemokines and growth factors was also variable. Taurine improved vestibular reflexes and limb muscular strength in perinatal rats and fine movements and immobility episodes in adult rats. These results show that chronic taurine administration partially alleviates the taiep neuropathology.

Exercise and Hippocampal Memory Systems.

No medications prevent or reverse age-related cognitive decline. Physical activity (PA) enhances memory in rodents, but findings are mixed in human studies. As a result, exercise guidelines specific for brain health are absent. Here, we re-examine results from human studies, and suggest the use of more sensitive tasks to evaluate PA effects on age-related changes in the hippocampus, such as relational memory and mnemonic discrimination. We discuss recent advances from rodent and human studies into the underlying mechanisms at both the central and peripheral levels, including neurotrophins and myokines that could contribute to improved memory. Finally, we suggest guidelines for future research to help expedite well-founded PA recommendations for the public.

Running Changes the Brain: the Long and the Short of It.

Exercise is a simple intervention that profoundly benefits cognition. In rodents, running increases neurogenesis in the hippocampus, a brain area important for memory. We describe the dynamic changes in new neuron number and afferent connections throughout their maturation. We highlight the effects of exercise on the neurotransmitter systems involved, with a focus on the role of glutamate and acetylcholine in the initial development of new neurons in the adult brain.

Running reorganizes the circuitry of one-week-old adult-born hippocampal neurons.

Adult hippocampal neurogenesis is an important form of structural and functional plasticity in the mature mammalian brain. The existing consensus is that GABA regulates the initial integration of adult-born neurons, similar to neuronal development during embryogenesis. Surprisingly, virus-based anatomical tracing revealed that very young, one-week-old, new granule cells in male C57Bl/6 mice receive input not only from GABAergic interneurons, but also from multiple glutamatergic cell types, including mature dentate granule cells, area CA1-3 pyramidal cells and mossy cells. Consistently, patch-clamp recordings from retrovirally labeled new granule cells at 7-8 days post retroviral injection (dpi) show that these cells respond to NMDA application with tonic currents, and that both electrical and optogenetic stimulation can evoke NMDA-mediated synaptic responses. Furthermore, new dentate granule cell number, morphology and excitatory synaptic inputs at 7 dpi are modified by voluntary wheel running. Overall, glutamatergic and GABAergic innervation of newly born neurons in the adult hippocampus develops concurrently, and excitatory input is reorganized by exercise.

Running rewires the neuronal network of adult-born dentate granule cells.

Exercise improves cognition in humans and animals. Running increases neurogenesis in the dentate gyrus of the hippocampus, a brain area important for learning and memory. It is unclear how running modifies the circuitry of new dentate gyrus neurons to support their role in memory function. Here we combine retroviral labeling with rabies virus mediated trans-synaptic retrograde tracing to define and quantify new neuron afferent inputs in young adult male C57Bl/6 mice, housed with or without a running wheel for one month. Exercise resulted in a shift in new neuron networks that may promote sparse encoding and pattern separation. Neurogenesis increased in the dorsal, but not the ventral, dentate gyrus by three-fold, whereas afferent traced cell labeling doubled in number. Regional analysis indicated that running differentially affected specific inputs. Within the hippocampus the ratio of innervation from inhibitory interneurons and glutamatergic mossy cells to new neurons was reduced. Distal traced cells were located in sub-cortical and cortical regions, including perirhinal, entorhinal and sensory cortices. Innervation from entorhinal cortex (EC) was augmented, in proportion to the running-induced enhancement of adult neurogenesis. Within EC afferent input and short-term synaptic plasticity from lateral entorhinal cortex, considered to convey contextual information to the hippocampus was increased. Furthermore, running upregulated innervation from regions important for spatial memory and theta rhythm generation, including caudo-medial entorhinal cortex and subcortical medial septum, supra- and medial mammillary nuclei. Altogether, running may facilitate contextual, spatial and temporal information encoding by increasing adult hippocampal neurogenesis and by reorganization of new neuron circuitry.

Adult Hippocampal Neurogenesis, Aging and Neurodegenerative Diseases: Possible Strategies to Prevent Cognitive Impairment.

The adult brain of humans and other mammals continuously generates new neurons throughout life. However, this neurogenic capacity is limited to two brain areas, the dentate gyrus (DG of the hippocampus and the subventricular zone (SVZ of the lateral ventricle. Although the DG generates new neurons, its neurogenic capacity declines with age and neurodegenerative diseases such as Alzheimer's disease (AD and Huntington's disease (HD. This review focuses on the role of newly-born neurons in cognitive processes, and discusses some of the strategies proposed in humans and animals to enhance neurogenesis and counteract age-related cognitive deficits, such as physical exercise and intake of natural products like omega-3 fatty acids, curcumin and flavanols.

Bridging animal and human models of exercise-induced brain plasticity.

Significant progress has been made in understanding the neurobiological mechanisms through which exercise protects and restores the brain. In this feature review, we integrate animal and human research, examining physical activity effects across multiple levels of description (neurons up to inter-regional pathways). We evaluate the influence of exercise on hippocampal structure and function, addressing common themes such as spatial memory and pattern separation, brain structure and plasticity, neurotrophic factors, and vasculature. Areas of research focused more within species, such as hippocampal neurogenesis in rodents, also provide crucial insight into the protective role of physical activity. Overall, converging evidence suggests exercise benefits brain function and cognition across the mammalian lifespan, which may translate into reduced risk for Alzheimer's disease (AD) in humans.

Functional circuits of new neurons in the dentate gyrus.

The hippocampus is crucial for memory formation. New neurons are added throughout life to the hippocampal dentate gyrus (DG), a brain area considered important for differential storage of similar experiences and contexts. To better understand the functional contribution of adult neurogenesis to pattern separation processes, we recently used a novel synapse specific trans-neuronal tracing approach to identify the (sub) cortical inputs to new dentate granule cells (GCs). It was observed that newly born neurons receive sequential innervation from structures important for memory function. Initially, septal-hippocampal cells provide input to new neurons, including transient innervation from mature GCs as well as direct feedback from area CA3 pyramidal neurons. After about 1 month perirhinal (PRH) and lateral entorhinal cortex (LEC), brain areas deemed relevant to integration of novel sensory and environmental information, become substantial input to new GCs. Here, we review the developmental time-course and proposed functional relevance of new neurons, within the context of their unique neural circuitry.

All about running: synaptic plasticity, growth factors and adult hippocampal neurogenesis.

Accumulating evidence from animal and human research shows exercise benefits learning and memory, which may reduce the risk of neurodegenerative diseases, and could delay age-related cognitive decline. Exercise-induced improvements in learning and memory are correlated with enhanced adult hippocampal neurogenesis and increased activity-dependent synaptic plasticity. In this present chapter we will highlight the effects of physical activity on cognition in rodents, as well as on dentate gyrus (DG) neurogenesis, synaptic plasticity, spine density, neurotransmission and growth factors, in particular brain-derived nerve growth factor (BDNF).

Monosynaptic inputs to new neurons in the dentate gyrus.

Adult hippocampal neurogenesis is considered important for cognition. The integration of newborn dentate gyrus granule cells into the existing network is regulated by afferent neuronal activity of unspecified origin. Here we combine rabies virus-mediated retrograde tracing with retroviral labelling of new granule cells (21, 30, 60, 90 days after injection) to selectively identify and quantify their monosynaptic inputs in vivo. Our results show that newborn granule cells receive afferents from intra-hippocampal cells (interneurons, mossy cells, area CA3 and transiently, mature granule cells) and septal cholinergic cells. Input from distal cortex (perirhinal (PRH) and lateral entorhinal cortex (LEC)) is sparse 21 days after injection and increases over time. Patch-clamp recordings support innervation by the LEC rather than from the medial entorhinal cortex. Mice with excitotoxic PRH/LEC lesions exhibit deficits in pattern separation but not in water maze learning. Thus, PRH/LEC input is an important functional component of new dentate gyrus neuron circuitry.

Physiology and pathology of calcium signaling in the brain.

Calcium (Ca(2+)) plays fundamental and diversified roles in neuronal plasticity. As second messenger of many signaling pathways, Ca(2+) as been shown to regulate neuronal gene expression, energy production, membrane excitability, synaptogenesis, synaptic transmission, and other processes underlying learning and memory and cell survival. The flexibility of Ca(2+) signaling is achieved by modifying cytosolic Ca(2+) concentrations via regulated opening of plasma membrane and subcellular Ca(2+) sensitive channels. The spatiotemporal patterns of intracellular Ca(2+) signals, and the ultimate cellular biological outcome, are also dependent upon termination mechanism, such as Ca(2+) buffering, extracellular extrusion, and intra-organelle sequestration. Because of the central role played by Ca(2+) in neuronal physiology, it is not surprising that even modest impairments of Ca(2+) homeostasis result in profound functional alterations. Despite their heterogeneous etiology neurodegenerative disorders, as well as the healthy aging process, are all characterized by disruption of Ca(2+) homeostasis and signaling. In this review we provide an overview of the main types of neuronal Ca(2+) channels and their role in neuronal plasticity. We will also discuss the participation of Ca(2+) signaling in neuronal aging and degeneration.

Mixed electrical-chemical transmission between hippocampal mossy fibers and pyramidal cells.

Morphological and electrophysiological studies have shown that granule cell axons, the mossy fibers (MFs), establish gap junctions and therefore electrical communication among them. That granule cells express gap junctional proteins in their axons suggests the possibility that their terminals also express them. If this were to be the case, mixed electrical-chemical communication could be supported, as MF terminals normally use glutamate for fast communication with their target cells. Here we present electrophysiological studies in the rat and modeling studies consistent with this hypothesis. We show that MF activation produced fast spikelets followed by excitatory postsynaptic potentials in pyramidal cells (PCs), which, unlike the spikelets, underwent frequency potentiation and were strongly depressed by activation of metabotropic glutamate receptors, as expected from transmission of MF origin. The spikelets, which persisted during blockade of chemical transmission, were potentiated by dopamine and suppressed by the gap junction blocker carbenoxolone. The various waveforms evoked by MF stimulation were replicated in a multi-compartment model of a PC by brief current-pulse injections into the proximal apical dendritic compartment, where MFs are known to contact PCs. Mixed electrical and glutamatergic communication between granule cells and some PCs in CA3 may ensure the activation of sets of PCs, bypassing the strong action of concurrent feed-forward inhibition that granule cells activate. Importantly, MF-to-PC electrical coupling may allow bidirectional, possibly graded, communication that can be faster than chemical synapses and subject to different forms of modulation.

Excitation-inhibition balance in the CA3 network--neuronal specificity and activity-dependent plasticity.

Activation of the axons of the granule cells, the mossy fibers, excites pyramidal cells and interneurons in the CA3 area, which, in turn, inhibit pyramidal cells. The integration of the various inputs that converge onto CA3 cells has been studied by pharmacological dissection of either the excitatory or inhibitory components. This strategy has the disadvantage of partially isolating the recorded cell from the network, ignoring the sources and the impact of concurrent inputs. To overcome this limitation, we dissociated excitatory and inhibitory synaptic conductances by mathematical extraction techniques, and analysed the dynamics of the integration of excitatory and inhibitory inputs in pyramidal cells and stratum lucidum interneurons (Sl-Ints) of CA3. We have uncovered a shunting mechanism that decreases the responsiveness of CA3 output cells to mossy fiber input after a period of enhanced excitability. The activation of the dentate gyrus (DG) after applying a kindling-like protocol in vitro, or after producing one or several seizures in vivo, results in a graded and reversible increase of inhibitory conductances in pyramidal cells, while in Sl-Ints, an increase of excitatory conductances occurs. Thus, interneurons reach more depolarized membrane potentials on DG activation yielding a high excitatory postsynaptic potential-spike coupling, while the contrary occurs in pyramidal cells. This effective activation of feedforward inhibition is synergized by the emergence of direct DG-mediated inhibition on pyramidal cells. These factors force the synaptic conductance to peak at a potential value close to resting membrane potential, thus producing shunt inhibition and decreasing the responsiveness of CA3 output cells to mossy fiber input.

Beta/gamma oscillatory activity in the CA3 hippocampal area is depressed by aberrant GABAergic transmission from the dentate gyrus after seizures.

Oscillatory activity in the CA3 region is thought to be involved in the encoding and retrieval of information. These oscillations originate from the recurrent excitation between pyramidal cells that are entrained by the synchronous rhythmic inhibition of local interneurons. We show here that, after seizures, the dentate gyrus (DG) tonically inhibits beta/gamma (20-24 Hz) field oscillations in the CA3 area through GABA-mediated signaling. These oscillations originate in the interneuron network because they are maintained in the presence of ionotropic glutamate receptor antagonists, and they can be blocked by GABA(A) receptor antagonists or by perfusion of a calcium-free extracellular medium. Inhibition of this oscillatory activity requires intact DG-to-CA3 connections, and it is suppressed by the activation of metabotropic glutamate receptors (mGluR). The influence of mGluR activation was reflected in the spontaneous subthreshold membrane oscillations of CA3 interneurons after one seizure but could also be observed in pyramidal cells after several seizures. Coincident stimulation of the DG at and beta/gamma frequencies produced a frequency-dependent excitation of interneurons and the inhibition of pyramidal cells. Indeed, these effects were maximal at the frequency that matched the mGluR-sensitive spontaneous field oscillations, suggesting a resonance phenomenon. Our results shed light on the mechanisms that may underlie the deficits in memory and cognition observed after epileptic seizures.

Blockade of the membranal GABA transporter potentiates GABAergic responses evoked in pyramidal cells by mossy fiber activation after seizures.

The presence of a neurotransmitter within a synaptic terminal is normally due to its local synthesis. However, uptake of the neurotransmitter from the extracellular milieu by a specific membranal transporter can also explain its intraterminal accumulation. A specific vesicular transporter carries the neurotransmitter into synaptic vesicles, enabling it to be released in a calcium-dependent manner when the terminal is invaded by an action potential. Under certain circumstances, a neurotransmitter can also be released by the reversal in the direction of its membranal transporter, in a calcium-independent manner. Interestingly, gamma-aminobutyric acid (GABA) can be released in this manner after epileptic activity. With intracellular recordings, in this work we show that in rats subjected to seizures, but not in naive rats, mossy fiber stimulation in the presence of glutamate receptor blockers produces bicuculline-sensitive inhibitory postsynaptic potentials (IPSPs) in pyramidal cells. The blockade of the membranal GABA transporter (GAT-1) strongly enhances the amplitude and decay time of the IPSPs in both high and low extracellular calcium concentrations. This electrophysiological evidence, together with previous neurochemical and immunohistological data, show that GAT-1 contributes to the termination of the synaptic action of mossy fiber-released GABA and rules out its involvement in depolarization-dependent GABA release.

Plasticity of the GABAergic phenotype of the "glutamatergic" granule cells of the rat dentate gyrus.

The "glutamatergic" granule cells of the dentate gyrus transiently express a GABAergic phenotype when a state of hyperexcitability is induced in the adult rat. Consequently, granule cell (GC) activation provokes monosynaptic GABAergic responses in their targets of area CA3. Because GABA exerts a trophic action on neonatal CA3 and mossy fibers (MF) constitute its main input, we hypothesized that the GABAergic phenotype of the MF could also be transiently expressed early in life. We addressed this possibility with a multidisciplinary approach. Electrophysiological recordings in developing rats revealed that, until day 22-23 of age, glutamate receptor antagonists block the excitatory response evoked in pyramidal cells by GCs, isolating a fast metabotropic glutamate receptor-sensitive GABAergic response. In a clear-cut manner from day 23-24 of age, GC activation in the presence of glutamatergic antagonists was unable to evoke synaptic responses in CA3. Immunohistological experiments showed the presence of GABA and GAD67 (glutamate decarboxylase 67 kDa isoform) in the developing GCs and their MF, and, using reverse transcription-PCR, we confirmed the expression of vesicular GABA transporter mRNA in the developing dentate gyrus and its downregulation in the adult. The GABAergic markers were upregulated and MF inhibitory transmission reappeared when hyperexcitability was induced in adult rats. Our data evidence for the first time a developmental and activity-dependent regulation of the complex phenotype of the GC. At early ages, the GABAergic input from the MF may add to the interneuronal input to CA3 to foster development, and, in the adult, it can possibly protect the system from enhanced excitability.

Activity-dependent induction of multitransmitter signaling onto pyramidal cells and interneurons of hippocampal area CA3.

The granule cells of the dentate gyrus (DG) are considered to be glutamatergic, but they contain glutamic acid decarboxylase, gamma-amino butyric acid (GABA), and the vesicular GABA transporter mRNA. Their expression is regulated in an activity-dependent manner and coincides with the appearance of GABAergic transmission from the mossy fibers (MF) to pyramidal cells in area CA3. These data support the hypothesis that MF are able to release glutamate and GABA. Following the principle that a given neuron releases the same neurotransmitter(s) onto all its targets, we here demonstrate the emergence, after a generalized convulsive seizure, of MF GABAergic signaling sensitive to activation mGluR-III onto pyramidal cells and interneurons of CA3. Despite this, excitation overrides inhibition in interneurons, preventing disinhibition. Furthermore, on blockade of GABA and glutamate ionotropic receptors, an M1-cholinergic depolarizing signal is also revealed in both targets, which postsynaptically modulates the glutamatergic and GABAergic fast neurotransmission. The emergence of these nonglutamatergic signals depends on protein synthesis. In contrast to cholinergic responses evoked by associational/commissural fibers activation, cholinergic transmission evoked by DG stimulation is only observed after seizures and is strongly depressed by the activation of mGluR-II, whereas both are depressed by M2-AChR activation. With immunohistological experiments, we show that this cholinergic pathway runs parallel to the MF. Thus seizures compromise a delicate balance of excitation and inhibition, on which a complex interaction of different neurotransmitters emerges to counteract excitation at pre- and postsynaptic sites. Particularly, MF GABAergic inhibition emerges to exert an overall inhibitory action on CA3.