Following peripheral nerve injury comprising a segmental defect, the extent of axon regeneration decreases precipitously with increasing gap length. Schwann cells play a key role in driving axon re-growth by forming aligned tubular guidance structures called bands of Büngner, which readily occurs in distal nerve segments as well as within autografts – currently the most reliable clinically-available bridging strategy. However, host Schwann cells generally fail to infiltrate large-gap acellular scaffolds, resulting in markedly inferior outcomes and motivating the development of next-generation bridging strategies capable of fully exploiting the inherent pro-regenerative capability of Schwann cells. We sought to create preformed, implantable Schwann cell-laden microtissue that emulates the anisotropic structure and function of naturally-occurring bands of Büngner. Accordingly, we developed a biofabrication scheme leveraging biomaterial-induced self-assembly of dissociated rat primary Schwann cells into dense, fiber-like three-dimensional bundles of Schwann cells and extracellular matrix within hydrogel micro-columns. This engineered microtissue was found to be biomimetic of morphological and phenotypic features of endogenous bands of Büngner, and also demonstrated 8 and 2× faster rates of axonal extension in vitro from primary rat spinal motor neurons and dorsal root ganglion sensory neurons, respectively, compared to 3D matrix-only controls or planar Schwann cells. To our knowledge, this is the first report of accelerated motor axon outgrowth using aligned Schwann cell constructs. For translational considerations, this microtissue was also fabricated using human gingiva-derived Schwann cells as an easily accessible autologous cell source. These results demonstrate the first tissue engineered bands of Büngner (TE-BoBs) comprised of dense three-dimensional bundles of longitudinally aligned Schwann cells that are readily scalable as implantable grafts to accelerate axon regeneration across long segmental nerve defects.
Recent research has identified the lateral habenula (LHb) as a brain region playing an important role in the production of stressful and anxiogenic states. Additionally, norepinephrine (NE) has long been known to be involved in arousal, stress and anxiety, and NE projections to the LHb have been identified emanating from the locus coeruleus (LC). The current research was devised to test the hypothesis that NE release within the LHb contributes to the occurrence of anxiogenic behaviors. Male rats were implanted with bilateral guide cannula aimed at the LHb and subsequently treated with intracranial (IC) infusions of the selective α adrenergic autoreceptor agonist, dexmedetomidine (DEX) (0, 0.5, 1.0 μg/side), prior to assessment of ambulatory and anxiogenic behavior in tests of spontaneous locomotion, open field behavior, and acoustic startle-response. Results demonstrated that DEX administration significantly reduced the overall locomotor behavior of subjects at both doses indicating that infusion of even small doses of this α agonist into the LHb can have profound effects on the subjects' general levels of alertness and activity. DEX was also found to attenuate anxiety as evidenced by a reduction in the magnitude of a startle-response to an acoustic 110 dB stimulus. Taken together, these results identify a role for NE release within the LHb in both arousal and anxiety.
The rostral migratory stream (RMS) facilitates neuroblast migration from the subventricular zone to the olfactory bulb throughout adulthood. Brain lesions attract neuroblast migration out of the RMS, but resultant regeneration is insufficient. Increasing neuroblast migration into lesions has improved recovery in rodent studies. We previously developed techniques for fabricating an astrocyte-based Tissue-Engineered RMS (TE-RMS) intended to redirect endogenous neuroblasts into distal brain lesions for sustained neuronal replacement. Here, we demonstrate that astrocyte-like-cells can be derived from adult human gingiva mesenchymal stem cells and used for TE-RMS fabrication. We report that key proteins enriched in the RMS are enriched in TE-RMSs. Furthermore, the human TE-RMS facilitates directed migration of immature neurons in vitro. Finally, human TE-RMSs implanted in athymic rat brains redirect migration of neuroblasts out of the endogenous RMS. By emulating the brain’s most efficient means for directing neuroblast migration, the TE-RMS offers a promising new approach to neuroregenerative medicine.
Neurogenesis in the postnatal mammalian brain is known to occur in the dentate gyrus of the hippocampus and the subventricular zone. These neurogenic niches serve as endogenous sources of neural precursor cells that could potentially replace neurons that have been lost or damaged throughout the brain. As an example, manipulation of the subventricular zone to augment neurogenesis has become a popular strategy for attempting to replace neurons that have been lost due to acute brain injury or neurodegenerative disease. In this review article, we describe current experimental strategies to enhance the regenerative potential of endogenous neural precursor cell sources by enhancing cell proliferation in neurogenic regions and/or redirecting migration, including pharmacological, biomaterial, and tissue engineering strategies. In particular, we discuss a novel replacement strategy based on exogenously biofabricated "living scaffolds" that could enhance and redirect endogenous neuroblast migration from the subventricular zone to specified regions throughout the brain. This approach utilizes the first implantable, biomimetic tissue-engineered rostral migratory stream, thereby leveraging the brain's natural mechanism for sustained neuronal replacement by replicating the structure and function of the native rostral migratory stream. Across all these strategies, we discuss several challenges that need to be overcome to successfully harness endogenous neural precursor cells to promote nervous system repair and functional restoration. With further development, the diverse and innovative tissue engineering and biomaterial strategies explored in this review have the potential to facilitate functional neuronal replacement to mitigate neurological and psychiatric symptoms caused by injury, developmental disorders, or neurodegenerative disease.
Recent work has implicated the Lateral Habenula (LHb) in the production of anxiogenic and aversive states. It is innervated by all the major monoamine neurotransmitter systems and has projections that have been shown to modulate the activity of both dopaminergic and serotonergic brain regions. Cocaine is a stimulant drug of abuse that potentiates neurotransmission in these monoamine systems and recent research suggests that the drug's behavioral effects may be related in part to its actions within the LHb. The present research was therefore devised to test the hypothesis that alterations in serotonin (5-HT) function within the LHb can affect the behavioral response to cocaine. Male rats were fitted with intracranial guide cannula and trained to traverse a straight alleyway once a day for a 1 mg/kg i.v. injection of cocaine. Intra-LHb pretreatment with the 5-HT agonist CP 94,253 (0, 0.1, or 0.25 μg/side) attenuated the development of approach/avoidance "retreat" behaviors known to be a consequence of cocaine's dual rewarding (approach) and anxiogenic (avoidance) properties. This effect was reversed by co-administration of a selective 5-HT antagonist, NAS-181 (0.1 μg/side), demonstrating drug specificity at the 5-HT receptor. These data suggest that 5-HT signaling within the LHb contributes to the anxiogenic effects of cocaine.
Rationale Cocaine produces significant aversive/anxiogenic actions whose underlying neurobiology remains unclear. A possible substrate contributing to these actions is the serotonergic (5-HT) pathway projecting from the dorsal raphé (DRN) to regions of the extended amygdala, including the Bed Nucleus of the Stria Terminalis (BNST) which have been implicated in the production of anxiogenic states. Objectives The present study examined the contribution of 5-HT signaling within the BNST to the anxiogenic effects of cocaine as measured in a runway model of drug self-administration. Methods Male Sprague-Dawley rats were fitted with bilateral infusion cannula aimed at the BNST and then trained to traverse a straight alley once a day for a single 1mg/kg i.v. cocaine infusion delivered upon goal-box entry on each of 16 consecutive days/trials. Intracranial infusions of CP 94,253 (0, 0.25, 0.5, or 1.0μg/side) were administered to inhibit local 5-HT release via activation of 5-HT1B autoreceptors. To confirm receptor specificity, the effects of this treatment were then challenged by co-administration of the selective 5-HT1B antagonist NAS-181. Results Intra-BNST infusions of the 5-HT1B autoreceptor agonist attenuated the anxiogenic effects of cocaine as reflected by a decrease in runway approach-avoidance conflict behavior. This effect was reversed by the 5-HT1B antagonist. Neither start latencies (a measure of the subject’s motivation to seek cocaine) nor spontaneous locomotor activity (an index of motoric capacity) were altered by either treatment. Conclusions Inhibition of 5-HT1B signaling within the BNST selectively attenuated the anxiogenic effects of cocaine, while leaving unaffected the positive incentive properties of the drug.
Cocaine administration has been shown to produce immediate positive (rewarding) and subsequent negative (anxiogenic) effects in humans and animals. These dual and opposing affective responses have been more difficult to demonstrate with administration of methamphetamine (meth). While animal studies have reliably demonstrated the positive reinforcing effects of the drug, reports of negative aftereffects following acute exposure have been few in number and contradictory in nature. The current research was devised to assess the effects of acute meth using a runway model of self-administration that is uniquely sensitive to both the positive and negative effects of a drug reinforcer in the same animal on the same trial. Male rats were allowed to traverse a straight alley once a day for 16 consecutive days/trials where entry into the goal box resulted in a single IV injection of meth (0.25, 0.5 or 1.0 mg/kg/inj.). The chosen doses were confirmed to be psychoactive as they produced dose-dependent increases in motoric/locomotor activation in these same subjects. The results demonstrated a U-shaped dose-response curve for the reinforcing effects of meth in that the intermediate dose group (0.5 mg/kg) produced the strongest approach behavior in the runway. Unlike other psychomotor stimulants, like cocaine, animals running for IV meth exhibited no evidence of any significant approach-avoidance behaviors reflective of the drug's negative anxiogenic effects. These results suggest that the abuse potential for meth is likely higher than for other shorter-acting psychomotor stimulants and reaffirms the utility of the runway procedure as a screen for a substance's abuse potential.
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