Reduced Inhibition within Layer IV of Sert Knockout Rat Barrel Cortex is Associated with Faster Sensory Integration

Abstract

Neural activity is essential for the maturation of sensory systems. In the rodent primary somatosensory cortex (S1), high extracellular serotonin (5-HT) levels during development impair neural transmission between the thalamus and cortical input layer IV (LIV). Rodent models of impaired 5-HT transporter (SERT) function show disruption in their topological organization of S1 and in the expression of activity-regulated genes essential for inhibitory cortical network formation. It remains unclear how such alterations affect the sensory information processing within cortical LIV. Using serotonin transporter knockout (Sert−/−) rats, we demonstrate that high extracellular serotonin levels are associated with impaired feedforward inhibition (FFI), fewer perisomatic inhibitory synapses, a depolarized GABA reversal potential and reduced expression of KCC2 transporters in juvenile animals. At the neural population level, reduced FFI increases the excitatory drive originating from LIV, facilitating evoked representations in the supragranular layers II/III. The behavioral consequence of these changes in network excitability is faster integration of the sensory information during whisker-based tactile navigation, as Sert−/− rats require fewer whisker contacts with tactile targets and perform object localization with faster reaction times. These results highlight the association of serotonergic homeostasis with formation and excitability of sensory cortical networks, and consequently with sensory perception.

Development of adaptive motor control for tactile navigation

“…The spontaneous tactile object localization (Celikel and Sakmann, 2007) experiments were performed on 11 male Wistar rats (Harlan Laboratories, The Netherlands). Animal handling, behavioral observations and behavioral experiment paradigm were as described before (Azarfar et al, 2018b) and were comparable to the previous studies utilizing the same task (Celikel and Sakmann, 2007;Voigts et al, 2008Voigts et al, , 2015Pang et al, 2011;Juczewski et al, 2016;Miceli et al, 2017). In short, on this task animals shuttle between two elevated platforms with a variable distance between them as a camera placed over the gap between the two platforms is used to visualize the body and whisker position ( Fig.1A).…”

“…14.5+ cm for adults and 9+ cm for juvenile, were used for further analysis. These distances were selected to ensure that only tactile exploration of whisker touch was quantified, as animals also use the touch receptors around their nose in shorter gapdistances (Celikel and Sakmann, 2007;Voigts et al, 2008Voigts et al, , 2015Pang et al, 2011;Juczewski et al, 2016;Miceli et al, 2017). Whisker protraction was quantified in respect to the midpoint of the whisk space which was defined by the most protracted and retracted positions, normalized to the nose position, during the tactile exploration epoch.…”

“…Considering that body and whisker positional control mature in parallel, it's tempting to speculate that sensorimotor computations that allow animals to adaptively control the position of their whiskers based on the recent sensory information also emerge by the end of the third week. Here, we experimentally tested this hypothesis using publicly available (Azarfar et al, 2018b) high-speed videography recordings of rats performing a tactile object localization task on the gap-crossing task (Hutson and Masterton, 1986;Celikel and Sakmann, 2007;Voigts et al, 2008Voigts et al, , 2015Pang et al, 2011;Juczewski et al, 2016;Miceli et al, 2017). Rats performed object localization first as a juvenile (P21) and later as adults (~P65).…”

Neocortical Microdissection at Columnar and Laminar Resolution for Molecular Interrogation

“…Finally, if the experimental design requires targeted alteration of molecular/cellular function, upon, e.g., sensory deprivation (Celikel et al, 2004;Foeller, Celikel, & Feldman, 2005), induction of synaptic plasticity in identified pathways (Allen et al, 2003;Clem, Celikel, & Barth, 2008), systematic modulation of cellular excitability (Huang et al, 2016;Juczewski et al, 2016;Miceli et al, 2017), circuit alterations (Corsini et al, 2009;Freudenberg et al, 2013aFreudenberg et al, , 2013bFreudenberg et al, , 2016Seib et al, 2013), or behavioral training (Celikel & Sakmann, 2007;Seib et al, 2013;Voigts, Herman, & Celikel, 2015), it would be advisable to design the experiments to ensure availability of within-animal and within-slice (wherever applicable) controls to minimize the genomic variability across independent samples and the experimental groups.…”

“…RNA and protein collected in this way is of sufficient quality to be used in high‐throughput techniques (i.e., RNA sequencing and mass spectrometry), making ABSM highly useful for the elucidation of molecular mechanisms in the brain. The method is easily applicable in any cellular/molecular or (neuro)physiology lab, as it is an expansion of the acute electrophysiological slice preparation commonly used in the central nervous system (see, e.g., Allen, Celikel, & Feldman, ; Celikel et al., ; Celikel, Szostak, & Feldman, ; Huang, Resnik, Celikel, & Englitz, ; Miceli et al., ). Because the method uses living tissue, ABSM has several advantages over other tissue isolation techniques (see Commentary).…”