[EN]This Doctoral Thesis addressed whether SSA is a common property along the auditory pathway and determine the set of afferent projections to SSA recording sites in the IC as well as the role of cholinergic inputs in shaping SSA responses. The results were compiled in six studies entitled: Study I. Frequency discrimination and stimulus deviance in the inferior colliculus and cochlear nucleus. Yaneri Aguilar Ayala, David Pérez-González, Daniel Duque Doncos, Israel Nelken, Manuel Sánchez Malmierca. Frontiers in Neural Circuits. 2013 Jan 14;6:119. DOI: 10.3389/fncir.2012.00119. eCollection 2012. Study II. Stimulus-specific adaptation and deviance detection in the inferior colliculus. Yaneri Aguilar Ayala, Manuel Sánchez Malmierca. Journal: Frontiers in Neural Circuits. 2013 Jan 17;6:89. DOI: 10.3389/fncir.2012.00089. eCollection 2012. Study III. Differences in the strength of cortical and brainstem inputs to SSA and non-SSA neurons in the inferior colliculus. Yaneri Aguilar Ayala, Adanna Udeh, Kelsey Dutta, Deborah Bishop, Manuel Sánchez Malmierca, Douglas L. Oliver. Scientific Reports. 5:10383 DOI: 10.1038/srep10383 Study IV. Cholinergic modulation of stimulus-specific adaptation in the inferior colliculus. Yaneri Aguilar Ayala, Manuel S. Malmierca. Submitted. Study V. Deviance detection in auditory subcortical structures: what can we learn from neurochemistry and neural connectivity? Daniel Duque Doncos*, Yaneri Aguilar Ayala*, Manuel Sánchez Malmierca. *Equal contribution. Journal: Cell and Tissue Research. 2015 Mar 8. DOI: 10.1007/s00441-015-2134-7 Study VI. Stimulus-specific adaptation in the inferior colliculus: The role of excitatory, inhibitory and modulatory inputs. Yaneri Aguilar Ayala*, David Pérez-González*, Manuel S. Malmierca. *Equal contribution. Biological Psychology. pii: S0301-0511(15)30022-3. doi: 10.1016/j.biopsycho.2015.06.016. The results support the conclusion that SSA is not a ubiquitous property found throughout the auditory brain but rather is a property that appears in the IC and forebrain. Cochlear nucleus neurons failed to adapt to high-probability sounds even when they were presented at high repetition rates (up to 20 Hz). On the other hand, IC neurons exhibit strong SSA responses even on the temporal scale of seconds, i.e., low repetition rates. Likewise, frequency discriminability of IC neurons reflects the extent of SSA they exhibit. SSA enhances deviant frequency saliency in the firing output of IC neurons by diminishing the response to repetitive sounds in a context-dependent manner.SSA was strongest in the non-lemniscal regions of the IC and was low or virtually absent in the lemniscal subdivision. The extent of SSA correlates with the broadness of the frequency response area in the IC neurons. Highly-adapting neurons exhibit wider spectral tuning (values as high as 30 ¿ 40 kHz) suggesting those neurons integrate across many more frequency inputs than those neurons with low or absent SSA. The spectral tuning and loci of SSA neurons is consistent with the denser dendritic arborization described for neurons of the cortices of the IC (Malmierca et al., 2011). The extensive dendritic arborization would allow more synaptic contacts to converge on SSA neurons allowing the integration of spectral information. In agreement with this, my retrograde tracer data demonstrated that SSA neurons are confined to IC regions that integrate dense cortical inputs from multiple auditory cortical areas, whereas sites of non-SSA neurons are strongly innervated by brainstem projections. Also, SSA recording sites receive inputs from the central nucleus of the IC (ICC), which are likely to convey ascending spectral information from brainstem nuclei. Collateral axons from ICC neurons may terminate on the SSA neurons en route to the brachium of the IC and medial geniculate body (Kudo and Niimi, 1980; Oliver et al., 1991; Saldana and Merchan, 1992; Malmierca et al., 1995a). Thus, the A1 and ICC projections as well as the broad response areas of SSA neurons support the suggestion that adapting neurons integrate feedforward inputs with different frequency selectivity and feedback inputs that modulate the extent of SSA. In this regard, previous work in our lab (Anderson et al., 2009) showed that the corticofugal projection exerts mainly a gain control over the SSA response, eliciting changes in SSA in either direction, increasing or decreasing it. However, very few SSA responses are generated de novo or abolished completely by inactivation of the cortical inputs. The diverse effects of cortical manipulation on SSA responses might be explained by direct A1 inputs to synaptic domains in IC that contain neurons with different SSA sensitivities. Likewise, changes in A1 excitability may affect SSA in the IC by triggering the release of acetylcholine through the disynaptic (A1 - pontomesencephalic tegmentum - IC) projection previously described (Motts and Schofield, 2009; Schofield, 2010). In agreement with the above discussion, my iontophoresis experiments demonstrated that acetylcholine exerts a baseline-dependent effect on SSA responses, exerting its greatest effect on IC neurons with intermediate SSA responses. Acetylcholine decreases the amount of SSA by increasing the response to the standard tone mainly through the activation of muscarinic receptors. A common mechanism by which acetylcholine modulates neural activity is by transiently disrupting the excitatory-inhibitory balance of neural circuits (Froemke, 2015). This unbalance can be achieved by modulating the release of neurotransmitters (Metherate, 2011), for example, by decreasing the release of GABA from interneurons (Salgado et al., 2007) or by eliciting the activation of NMDA receptor-mediated glutamatergic neurotransmission (Metherate and Hsieh, 2003; Metherate, 2004; Liang et al., 2008). Thus, local augmentation of acetylcholine contributes to the maintenance of the encoding of repetitive acoustical input by decreasing adaptation. Adjustment in the neural sensitivity in the IC to frequently occurring frequencies would contribute to boosting the bottom-up sensory information en route to the auditory cortex and agrees with the evidence that neuromodulators lead to enduring modifications of neural circuits via transient disinhibition (Froemke, 2015). Overall, the data from my doctoral thesis show that SSA neurons are in a position to integrate higher-level signals with incoming sensory information and that the filtering of sensory feedforward information is under a fast, top-down adjustment of IC neural sensitivity likely via a direct feedback loop from auditory cortical areas and by the indirect activation of cholinergic synaptic inputs.
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