Mismatch Negativity (MMN) in Freely-Moving Rats with Several Experimental Controls

Abstract

Mismatch negativity (MMN) is a scalp-recorded electrical potential that occurs in humans in response to an auditory stimulus that defies previously established patterns of regularity. MMN amplitude is reduced in people with schizophrenia. In this study, we aimed to develop a robust and replicable rat model of MMN, as a platform for a more thorough understanding of the neurobiology underlying MMN. One of the major concerns for animal models of MMN is whether the rodent brain is capable of producing a human-like MMN, which is not a consequence of neural adaptation to repetitive stimuli. We therefore tested several methods that have been used to control for adaptation and differential exogenous responses to stimuli within the oddball paradigm. Epidural electroencephalographic electrodes were surgically implanted over different cortical locations in adult rats. Encephalographic data were recorded using wireless telemetry while the freely-moving rats were presented with auditory oddball stimuli to assess mismatch responses. Three control sequences were utilized: the flip-flop control was used to control for differential responses to the physical characteristics of standards and deviants; the many standards control was used to control for differential adaptation, as was the cascade control. Both adaptation and adaptation-independent deviance detection were observed for high frequency (pitch), but not low frequency deviants. In addition, the many standards control method was found to be the optimal method for observing both adaptation effects and adaptation-independent mismatch responses in rats. Inconclusive results arose from the cascade control design as it is not yet clear whether rats can encode the complex pattern present in the control sequence. These data contribute to a growing body of evidence supporting the hypothesis that rat brain is indeed capable of exhibiting human-like MMN, and that the rat model is a viable platform for the further investigation of the MMN and its associated neurobiology.

Auditory cortical and hippocampal local-field potentials to frequency deviant tones in urethane-anesthetized rats: An unexpected role of the sound frequencies themselves

“…Furthermore, similarly to MMN (Jacobsen and Schröger, 2001), differential brain responses in animals have been attributed to deviant tones as changes in the repetitiveness of a standard tone rather than as rare tones relative to the standard tone (e.g., Ruusuvirta et al, 1998;Nakamura et al, 2011;Taaseh et al, 2011;Jung et al, 2013;Shiramatsu et al, 2013;Harms et al, 2014;Malmierca et al, 2014). Together, these findings suggest that the mechanisms for automatic auditory change detection are not limited to the human brain.…”

Sensory processing in autism spectrum disorders and Fragile X syndrome—From the clinic to animal models

“…Mismatch negativity (MMN) is another neural phenomenon reflecting underlying sensory filtering which is revealed by studying EEG responses to trains of auditory stimuli in humans (Näätänen et al, 2007) and rodents (Ehrlichman et al, 2008; Harms et al, 2014; Nakamura et al, 2011; Siegel et al, 2003; Witten et al, 2014). Unlike P1 suppression, PPI and habituation, which all dampen responses to less relevant stimuli, MMN involves the pre-attentive identification of more relevant stimuli among trains of less relevant ones.…”

“…Experimental approaches which measure sensory processing are emerging as powerful translational tools in this regard. Studies using EEG, magnetoencephalography (MEG) or startle/EMG point to analogous sensory processing deficits in humans and animal models (Castrén et al, 2003; Connolly et al, 2004; Ehrlichman et al, 2008; Ethridge et al, 2016; Harms et al, 2014; Lovelace et al, 2016; Maxwell et al, 2004; Nakamura et al, 2011; Siegel et al, 2003; Umbricht et al, 2004) and have facilitated examination of underlying mechanisms of sensory disorders in rodent models relevant to ASD/FXS. Furthermore, such studies take advantage of the properties of the neural circuitry underlying basic sensory processing, which is better characterized and may be more conserved across species than neural circuitry underlying complex social and communication behaviors.…”

Stimulus-specific adaptation in the inferior colliculus: The role of excitatory, inhibitory and modulatory inputs

“…The MMN is measured as the difference between the auditoryevoked potential elicited by a repetitive sound compared with the potential elicited by a rare, unexpected sound (larger amplitude) in electroencephalographic studies. MMN has been positioned as a potentially promising biomarker candidate for the diagnosis of pathologies such as schizophrenia (Harms et al, 2014;Nagai et al, 2013) or autism spectrum disorders, including Asperger's syndrome (e.g., O'Connor, 2012). Patients with schizophrenia exhibited a reduced ability to detect acoustic changes reflected in reduced MMN (Fisher, Grant, Smith, Borracci, Labelle, & Knott, 2012;Hong, Moran, Du, O'Donnell, & Summerfelt, 2012;Michie, 2001).…”

“…Thus, a starting point for elucidating how alterations in neurotransmission contribute to deficits in deviance detection is to employ animal models to pharmacologically isolate the role of specific modulatory substances on event-related potentials or on correlated neuronal activity. Recent studies have demonstrated that MMN-like responses occur in animal models like the rat (Harms et al, 2014;Jung et al, 2013). Likewise, neurons that exhibit a specific decrement in their response to repetitive but not to rare sounds have been characterized in animals.…”