A Late Critical Period for Frequency Modulated Sweeps in the Mouse Auditory System.

Neuronal circuits are shaped by experience during time windows of increased plasticity in postnatal development. In the auditory system, the critical period for the simplest sounds-pure frequency tones-is well defined. Critical periods for more complex sounds remain to be elucidated. We used in vivo electrophysiological recordings in the mouse auditory cortex to demonstrate that passive exposure to frequency modulated sweeps (FMS) from postnatal day 31 to 38 leads to long-term changes in the temporal representation of sweep directions. Immunohistochemical analysis revealed a decreased percentage of layer 4 parvalbumin-positive (PV+) cells during this critical period, paralleled with a transient increase in responses to FMS, but not to pure tones. Preventing the PV+ cell decrease with continuous white noise exposure delayed the critical period onset, suggesting a reduction in inhibition as a mechanism for this plasticity. Our findings shed new light on the dependence of plastic windows on stimulus complexity that persistently sculpt the functional organization of the auditory cortex.

Decreased thyroid hormone signaling accelerates the reinnervation of the optic tectum following optic nerve crush in adult zebrafish.

The regenerative capacity of the adult mammalian central nervous system (CNS) is poor and finding ways to stimulate long distance axonal regeneration in humans remains a challenge for neuroscientists. Thyroid hormones, well known for their key function in CNS development and maturation, more recently also emerged as molecules influencing regeneration. While several studies investigated their influence on peripheral nerve regeneration, in vivo studies on their role in adult CNS regeneration remain scarce. We therefore investigated the effect of lowering T3 signaling on the regeneration of the optic nerve (ON) following crush in zebrafish, a species where full recovery occurs spontaneously. Adult zebrafish were exposed to iopanoic acid (IOP), which lowered intracellular 3,5,3'-triiodothyronine (T3) availability, or to the thyroid hormone receptor ß antagonist methylsulfonylnitrobenzoate (C1). Both treatments accelerated optic tectum (OT) reinnervation. At 7days post injury (7dpi) there was a clear increase in the biocytin labeled area in the OT following anterograde tracing as well as an increased immunostaining of Gap43, a protein expressed in outgrowing axons. This effect was attenuated by T3 supplementation to IOP-treated fish. ON crush induced very limited cell death and proliferation at the level of the retina in control, IOP- and C1-treated fish. The treatments also had no effect on the mRNA upregulation of the regeneration markers gap43, tub1a, and socs3b at the level of the retina at 4 and 7dpi. We did, however, find a correlation between the accelerated OT reinnervation and a more rapid resolution of microglia/macrophages in the ON and the OT of IOP-treated fish. Taken together these data indicate that lowering T3 signaling accelerates OT reinnervation following ON crush in zebrafish and that this is accompanied by a more rapid resolution of the inflammatory response.

Role of thyroid hormones in different aspects of nervous system regeneration in vertebrates.

Spontaneous functional recovery from injury in the adult human nervous system is rare and trying to improve recovery remains a clinical challenge. Nervous system regeneration is a complicated sequence of events involving cell death or survival, cell proliferation, axon extension and remyelination, and finally reinnervation and functional recovery. Successful recovery depends on the cell-specific and time-dependent activation and repression of a wide variety of growth factors and guidance molecules. Thyroid hormones (THs), well known for their regulatory role in neurodevelopment, have recently emerged as important modulators of neuroregeneration. This review focuses on the endogenous changes in the proteins regulating TH availability and action in different cell types of the adult mammalian nervous system during regeneration as well as the impact of TH supplementation on the consecutive steps in this process. It also addresses possible differences in TH involvement between different vertebrate classes, early or late developmental stages and peripheral or central nervous system. The available data show that THs are able to stimulate many signaling pathways necessary for successful neurogeneration. They however also suggest that supplementation with T4 and/or T3 may have beneficial or detrimental influences depending on the dose and more importantly on the specific phase of the regeneration process.

Sequential Organization of Critical Periods in the Mouse Auditory System.

Critical periods-time windows of heightened plasticity in postnatal development-are specific to sensory features and are asynchronous. Whether they are timed by a temporally precise developmental program or are sequentially organized is not known. We use electrophysiology and molecular or sensory manipulations to elucidate the biological constraints on critical period timing. Passive sound exposure shows that the cortical representations of two sound features, pure tone and frequency-modulated sweep (FMS), are not influencing each other. Enhancing inhibition before the critical period for pure tone accelerates it without changing the critical period for FMS. Similarly, delaying the critical period for pure tone with white noise exposure has no effect on the critical period for FMS. However, the critical period for FMS starts only if the one for pure tone has occurred. Together, these results indicate that distinct critical periods, although sequentially organized, can be temporally shifted independently of each other.

Matrix metalloproteinases as promising regulators of axonal regrowth in the injured adult zebrafish retinotectal system.

Overcoming the failure of axon regeneration in the mammalian central nervous system (CNS) after injury remains a major challenge, which makes the search for proregenerative molecules essential. Matrix metalloproteinases (MMPs) have been implicated in axonal outgrowth during CNS development and show increased expression levels during vertebrate CNS repair. In mammals, MMPs are believed to alter the suppressive extracellular matrix to become more permissive for axon regrowth. We investigated the role of MMPs in axonal regeneration following optic nerve crush (ONC) in adult zebrafish, which fully recover from such injuries due to a high intrinsic axon growth capacity and a less inhibitory environment. Lowering general retinal MMP activity through intravitreal injections of GM6001 after ONC strongly reduced retinal ganglion cell (RGC) axonal regrowth, without influencing RGC survival. Based on a recently performed transcriptome profiling study, the expression pattern of four MMPs after ONC was determined via combined use of western blotting and immunostainings. Mmp-2 and -13a were increasingly present in RGC somata during axonal regrowth. Moreover, Mmp-2 and -9 became upregulated in regrowing RGC axons and inner plexiform layer (IPL) synapses, respectively. In contrast, after an initial rise in IPL neurites and RGC axons during the injury response, Mmp-14 expression decreased during regeneration. Altogether, a phase-dependent expression pattern for each specific MMP was observed, implicating them in axonal regrowth and inner retina remodeling after injury. In conclusion, these data suggest a novel, neuron-intrinsic function for multiple MMPs in axon regrowth that is distinct from breaking down environmental barriers. J. Comp. Neurol. 524:1472-1493, 2016. © 2015 Wiley Periodicals, Inc.