Background

Over the last few decades, there has been a tremendous increase in research linking sensory processing dysfunction with different neuropsychiatric disorders (Hornix et al., 2019) such as autism spectrum disorder (ASD), fragile X syndrome, post-traumatic stress disorder (PTSD), Rett Syndrome, schizophrenia, depression, anxiety and traumatic brain injury (TBI). It is interesting how typical cognitive difficulties of these neuropsychiatric disorders are more and more associated with alterations in the perception of the external world. One example of a specific sensory processing dysfunction that crosses the borders of several neuropsychiatric disorders is aberrant tactile sensitivity. Interestingly, it is estimated that about 90% of individuals diagnosed with ASD have atypical sensory experiences, described as both hyper- and hypo-reactivity, with abnormal responses to tactile stimulation (Marco et al., 2011).

Tactile sensory dysfunction is likely due to circuit dysfunction across the peripheral nervous system and the brain regions [e.g., primary somatosensory (S1) and thalamus] involved in processing and integration of tactile inputs (Hornix et al., 2019). Neural mechanisms underlying tactile sensitivity are not fully understood. However, recent studies using specific behavioral tasks and mouse model of neurological and neuropsychiatric disorders are considerably broadening our understanding of the neurobiological bases of tactile sensory impairments (McNamara et al., 2010, Orefice et al., 2016, He et al., 2017, Chelini et al., 2019). Moreover, the advent of next-generation approaches (i.e., optogenetics and chemo-genetics) in behavioral neuroscience have opened the door to test new hypotheses regarding the neural circuit involved in processing and integration of tactile inputs. To date only a limited number of behavioral tests have been developed for assessing tactile perception abnormalities in rodents [e.g., the whisker nuisance (WN) test and the tactile prepulse inhibition (tactile PPI) assay]. Therefore, there is a growing need for generating other behavioral tasks relevant to the tactile sensory dysfunctions.

One behavioral paradigm to evaluate tactile sensitivity in mice is the tactile PPI assay. This behavioral paradigm consists in delivering puffed air onto the back hairy skin of mice and is useful to specifically assess both hairy skin sensitivity and sensorimotor gating. A recent animal model study, by using the tactile PPI test, revealed how mice with mutations in Mecp2, Gabrb3, Shank3 or Fmr1 exhibit tactile hypersensitivity (Orefice et al., 2016).

Normal touch perception in the skin is mediated by the activation of cutaneous low-threshold mechanosensory neurons (LTMRs), which possess one peripheral axonal branch that innervates the skin and another branch that innervates the central nervous system (CNS). This task is valuable to study the circuit-level alterations related to the transmission of neuronal impulse between the LTMRs and the neurons of spinal cord that relay touch signaling to the sensory region of the brain.

However, sensory perception in mouse is also mediated by mystacial vibrissae (whiskers). Rodent whisker hair follicles are tactile organs functionally equivalent to human fingertips.

Rodent whiskers are exquisitely sensitive to touch and extract precise information about environment navigation, object recognition and social interactions. Afferent whisker information, via sensory nerve afferents, reaches layer IV of primary somatosensory cortex (SSp) for further processing (Petersen, 2007; Diamond et al., 2008).

Therefore, in our opinion, animal studies of tactile sensory processing must also consider whisker dependent tactile tasks, since whisker system is an important sensory organ essential to construction of the perceptual world.

Here, we provide a detailed and modified protocol of whisker nuisance (WN) test, to specifically assess tactile hypersensitivity relative to whisker stimulation in mouse. A previous WN test, considering seven different behavioral categories, was developed by McNamara and colleagues (McNamara et al., 2010) to assess sensory abnormalities in rats after diffuse brain injury. In rats, this test succeeded in demonstrating changes in sensory sensitivity after brain injury. Our modified version of WN test has revealed to be a valuable tool to evaluate whisker-dependent responses in mice in the absence of experimentally-induced lesions, as described in our recent work (Chelini et al., 2019).

We took advantage of Engrailed-2 knockout (En2-/-) mice, an informative model for understanding how neurodevelopmental defects can lead to cellular and circuit dysfunctions that directly or indirectly impact behaviors relevant to neuropsychiatric disorders.

Five different parameters are assessed during sensory stimulation in this test: fearful behavior, stance, breathing, response to stick and evasiveness. This test, together with previously developed sensory test, could represent a successful way to assess hyper-/hypo-sensitivity to sensory stimulation as well as to investigate the mechanisms underlying information processing during whisker-guided sensation in mouse, helping in shedding light to the sensory processing abnormalities found in human patients with neuropsychiatric and more in general with neurological disorders.