Functional Rehabilitation of Cadmium-Induced Neurotoxicity Despite Persistent Peripheral Pathophysiology in the Olfactory System

Abstract

Intranasal exposure to the heavy metal cadmium has been linked to olfactory dysfunction and neurotoxicity. Here, we combine optical imaging of in vivo neurophysiology, genetically defined anatomical tract tracing, mass spectrometry, and behavioral psychophysical methods to evaluate the persistent harmful effects of acute intranasal exposure to cadmium in a mouse model and to investigate the functional consequences of sensory rehabilitation training. We find that an acute intranasal instillation of cadmium chloride leads to an accumulation of cadmium in the brain's olfactory bulb that persists for at least 4 weeks. This is accompanied by persistent severe pathophysiology of the olfactory nerve, a gradual reduction in axonal projections from the olfactory epithelium, and complete impairment on an olfactory detection task. Remarkably, 2 weeks of odorant-guided operant conditioning training proved sufficient to restore olfactory detection performance to control levels in cadmium-exposed mice. Optical imaging from rehabilitated mice showed that this training did not cause any detectable restoration of olfactory nerve function, suggesting that the recovery of function was mediated by central neuroplasticity in which the brain learned to interpret the degraded sensory input. These data demonstrate that sensory learning can mask even severe damage from neurotoxicants and suggest that explicit sensory training may be useful in rehabilitation of olfactory dysfunction.

Intranasal exposure to manganese disrupts neurotransmitter release from glutamatergic synapses in the central nervous system in vivo

“…Perhaps because it is uniquely vulnerable to external toxicants, the olfactory system is highly plastic. This allows sensory learning to compensate for even severe toxicant-induced pathophysiology in the olfactory nerve (Czarnecki et al, 2012). Physiological techniques such as magnetic resonance imaging (Zald and Pardo 2000) or measurement of olfactory event-related potentials (Lötsch and Hummel, 2006; Scott and Scott-Johnson 2002) might thus reveal Mn-induced neurological deficits that are masked in conventional behavioral assays.…”

Persistent, generalized hypersensitivity of olfactory bulb interneurons after olfactory fear generalization

“…In vivo optical imaging was performed (Czarnecki, Moberly, Rubinstein, Turkel, Pottackal, & McGann, 2011; Czarnecki, Moberly, Turkel, Rubinstein, Pottackal, Rosenthal et al, 2012; Fast & McGann, 2017; Kass, Czarnecki, Moberly, & McGann, 2017; Kass, Guang, Moberly, & McGann, 2016; Kass, Moberly, & McGann, 2013a; Kass, Moberly, Rosenthal, Guang, & McGann, 2013b; Kass, Pottackal, Turkel, & McGann, 2013c; Kass et al, 2013d) to visualize odor-evoked GCaMP signals from GAD65-expressing PG interneurons (Figure 1G–I) before and after conditioning (Figure 1A). Vapor dilution olfactometry was used during imaging (Czarnecki et al, 2011; Czarnecki et al, 2012; Kass et al, 2017; Kass et al, 2016; Kass et al, 2013a; Kass et al, 2013b; Kass et al, 2013c; Kass et al, 2013d) to present up to 3 concentrations of up to 5 monomolecular odorants that have no known innate valence.…”

“…Vapor dilution olfactometry was used during imaging (Czarnecki et al, 2011; Czarnecki et al, 2012; Kass et al, 2017; Kass et al, 2016; Kass et al, 2013a; Kass et al, 2013b; Kass et al, 2013c; Kass et al, 2013d) to present up to 3 concentrations of up to 5 monomolecular odorants that have no known innate valence. The odor-panel was selected based on previous experiments (Kass et al, 2013b; Kass et al, 2013d), and included 3 esters (MV, which was used as the CS, EV, and BA), 1 ketone (2H), and 1 aldehyde (t rans -2-methyl-2-butenal, 2M2B), yielding 3 odor categories for paired and odor-alone subjects (training ester, unexposed esters, and unexposed “other”) and 1 odor category for shock-alone subjects (unexposed odors).…”

“…Optical signals were analyzed as previously reported (Czarnecki et al, 2011; Czarnecki et al, 2012; Fast & McGann, 2017; Kass et al, 2017; Kass et al, 2016; Kass et al, 2013a; Kass et al, 2013b; Kass et al, 2013c; Kass et al, 2013d). Odor-evoked response amplitudes (ΔF/Fs) were quantified as the change in fluorescence during the first inhalation of odor and as the integrated change from baseline fluorescence during the 6-sec odor presentation.…”

Fear Learning Enhances Neural Responses to Threat-Predictive Sensory Stimuli

“…Odorant-evoked spH signals, indicating neurotransmitter release from OSN terminals into olfactory bulb glomeruli, were visualized in vivo using wide-field fluorescence imaging through an implanted cranial window (12, 13) before and after behavioral training (Fig. 1A).…”