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Neural plasticity, which is the basis or learning and memory formation, declines continuously and progressively over the course of life. However, the molecular mechanisms underlying neuronal ageing and the decline of neural plasticity with age are not well understood. Sensory input and neural excitation have been shown to regulate organismal ageing processes and control lifespan, but how they drive the ageing of cognitive function and plasticity remains obscure. To study the mechanisms of how neuronal activity affects the decline of neural plasticity with age, I have established an assay in C. elegans based on its robust and reproducible behavioral responses to O2. Animals show O2 experience-dependent behavioral plasticity, where an overnight shift of the O2 concentration in the culture environment reprograms worms' O2-evoked speed responses. I show that long-term high neural activity of the O2-sensing neurons accelerates the decline of plasticity with age at both the neuronal and behavioral level. By gene expression profiling of O2- sensing neurons in ageing animals, I show that neuronal activity alters age-related changes in transcription, and the data suggest that neuronal resources undergo a redistribution during ageing that depends on the neuronal activity state. In particular, the differential expression of neuronal genes that modulate Ca2+ homeostasis plays a central role in mediating activity-dependent decline. Low activity neurons require the K+-dependent Na+/Ca2+ (NCKX) exchanger to remove intracellular Ca2+ in order to sustain plasticity with age, whereas the decline of plasticity associated with high neuronal activity acts through calmodulin and the scaffold protein Kidins220 (also known as ARMS). These findings demonstrate directly that the activity of neurons alters neuronal homeostasis to govern the age-related decline of neural plasticity and throw light on the mechanisms involved.

Until recently, obtaining rest-frame optical spectra of galaxies at z > 1 was a time consuming and challenging observation due to the difficult nature of near-infrared (near-IR) spectroscopy. However, with the advent of second generation ground-based near-IR spectrographs (e.g. KMOS, MOSFIRE), and the new low resolution near-IR grisms on the Hubble Space Telescope (HST), we have entered a new era in the study of high redshift galaxies. This thesis explores the physical properties of star-forming galaxies in the redshift range 1 < z < 3 by utilising a custom reduction of the 3D-HST near-IR grism spectroscopic survey. One of the most important observational constraints on the evolution of galaxies is the mass-metallicity relation (MZR), which is sensitive to both the star-formation history and various inflow/outflow processes. I use the 3D-HST spectra to provide a new constraint on the MZR at 2:0 < z < 2:3, and moreover measure the O/H abundance directly from the oxygen and hydrogen emission lines ([OII], [OIII] and Hβ) as opposed to the more common method at high redshift of inferring O/H from the N/H ratio (via [NII] and Hα). I show that the traditional form of the MZR is recovered from the 3D-HST data, with metallicity increasing with the stellar mass of a galaxy. However, the absolute metallicity values I derive are inconsistent with previous N/H-based measurements of metallicity at these redshifts. Moreover, I show that the 3D-HST data is inconsistent with the `fundamental metallicity relation' (FMR), and that, contrary to previous claims, this local Universe relation may not hold out to z & 2. To investigate this metallicity discrepancy further, I measure the evolution of the [OIII]/Hβ nebular emission line ratio in the 3D-HST spectra over the redshift range 1:3 < z < 2:3. I compare this observed line ratio evolution with state-of-the- art theoretical models which take into account the independent evolution of the ionization parameter, electron density and metallicity of star-forming regions with redshift. The homogeneous 3D-HST dataset allows me to perform a consistent analysis of this evolution which takes into account line luminosity selection effects. I show that, according to models, the observed [OIII]/Hβ evolution cannot be accounted for by pure metallicity evolution. Instead I am able to infer that the line ratio evolution is more consistent with, at the very least, an evolution to stronger ionizing conditions at high redshift, and perhaps even denser star-forming regions. I explore how this result can also explain the observed discrepancy between high redshift metallicity measurements. In light of this finding, I revisit the MZR at z >~ 2 and employ a purely theoretical approach to inferring metallicities from nebular lines, which is able to account for an evolution in ionization conditions. I then use a selection of galaxies from the local Universe, which mimic the properties of high redshift galaxies, to derive a more robust ionization sensitive, conversion, between N/H and O/H. With this new conversion which I am able to bring the previous inconsistent metallicity measurements at z >~ 2 back into agreement. Finally, I am able to show that, in this new formalism, the metallicity evolution between z = 2 and z = 3 is perhaps not as large as previously reported. To conclude I discuss ongoing work as part of the KMOS Deep Survey (KDS) being undertaken with the near near-IR Multi-Object Spectrograph KMOS on the VLT. I describe the observations and data reduction that has been completed to date and describe how this instrument will allow me to extend the work presented in this thesis to z > 3. I also introduce FIGS, a new HST near-IR grism survey seeking to spectroscopically identify galaxies at 5:5 < z < 8:5 and work I have begun in exploring this dataset.