Deletion or activation of the aryl hydrocarbon receptor alters adult hippocampal neurogenesis and contextual fear memory

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that mediates the toxicity of dioxin and serves multiple developmental roles. In the adult brain, while we now localize AhR mRNA to nestin-expressing neural progenitor cells in the dentate gyrus (DG) of the hippocampus, its function is unknown. This study tested the hypothesis that AhR participates in hippocampal neurogenesis and associated functions. AhR deletion and activation by the potent environmental toxicant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), adversely impacted neurogenesis and cognition. Adult AhR-deficient mice exhibited impaired hippocampal-dependent contextual fear memory while hippocampal-independent memory remained intact. AhR-deficient mice displayed reduced cell birth, decreased cell survival, and diminished neuronal differentiation in the DG. Following TCDD exposure, wild-type mice exhibited impaired hippocampal-dependent contextual memory, decreased cell birth, reduced neuronal differentiation, and fewer mature neurons in the DG. Glial differentiation and apoptosis were not altered in either TCDD-exposed or AhR-deficient mice. Finally, defects observed in TCDD-exposed mice were dependent on AhR, as TCDD had no negative effects in AhR-deficient mice. Our findings suggest that AhR should be further evaluated as a potential transcriptional regulator of hippocampal neurogenesis and function, though other sites of action may also warrant consideration. Moreover, TCDD exposure should be considered as an environmental risk factor that disrupts adult neurogenesis and potentially related memory processes.

Delayed effects of developmental exposure to low levels of the aryl hydrocarbon receptor agonist 3,3′,4,4′,5-pentachlorobiphenyl (PCB126) on adult zebrafish behavior

“…The AHR is expressed in the vertebrate brain at multiple life stages (Andreasen et al, 2002, Petersen et al, 2000, Williamson et al, 2005) and has an evolutionarily conserved role in neuronal development (Collins et al, 2008, Huang et al, 2004, Latchney et al, 2013, Qin and Powell-Coffman, 2004). In the zebrafish brain, dioxin exposure was found to cause induction of AHR2 (Andreasen et al, 2002) as well as its associated protein aryl hydrocarbon nuclear translocator (ARNT) (Tanguay et al, 2000).…”

“…Early exposure of zebrafish embryos to environmentally relevant concentrations of dioxin resulted in reduced brain volume and decreased expression of neurodevelopmental genes in larvae (Hill et al, 2003). In rodents, gestational exposure to dioxin causes AHR-dependent abnormal development in a number of areas in the brain, including the cerebellum, hippocampus, the midbrain and the early region of the forebrain that matures to control advanced brain functions (Collins et al, 2008, Latchney et al, 2013, Tanida et al, 2014, Williamson et al, 2005). These abnormalities often involve changes in neuronal development and establishment of neuron cell fate (Gohlke et al, 2009, Hays et al, 2002, Latchney et al, 2013, Nguyen et al, 2013b).…”

“…In rodents, gestational exposure to dioxin causes AHR-dependent abnormal development in a number of areas in the brain, including the cerebellum, hippocampus, the midbrain and the early region of the forebrain that matures to control advanced brain functions (Collins et al, 2008, Latchney et al, 2013, Tanida et al, 2014, Williamson et al, 2005). These abnormalities often involve changes in neuronal development and establishment of neuron cell fate (Gohlke et al, 2009, Hays et al, 2002, Latchney et al, 2013, Nguyen et al, 2013b). These effects do not occur in AHR-null mice, consistent with a role for AHR in mediating dioxin-induced alteration of neuronal differentiation (Gohlke et al, 2009, Latchney et al, 2013).…”

Excessive activation of AhR signaling disrupts neuronal migration in the hippocampal CA1 region in the developing mouse

“…In particular, AhR-null mice showed impaired neurogenesis in the developing cerebellum and adult hippocampus (Dever et al, 2016;Latchney et al, 2013). It should be noted that impairments of neurogenesis were observed by not only TCDD exposure (Collins et al, 2008), but also by AhR-null disruption (Dever et al, 2016, Latchney et al, 2013. Further studies are needed to elucidate the mechanism of AhR-mediated regulation of neurogenesis during mammalian brain development.…”

“…Thus, it is reasonable to speculate that the mechanism of the CA-AhRmediated impairment of neurogenesis is similar to the one induced by TCDD exposure. In particular, AhR-null mice showed impaired neurogenesis in the developing cerebellum and adult hippocampus (Dever et al, 2016;Latchney et al, 2013). It should be noted that impairments of neurogenesis were observed by not only TCDD exposure (Collins et al, 2008), but also by AhR-null disruption (Dever et al, 2016, Latchney et al, 2013.…”