Early Exposure to Environmental Toxin Raises Risk of Future Harm
Baher A. Ibrahim, Jeremy J. Louie, Yoshitaka Shinagawa, Gang Xiao, Alexander R. Asilador, et al.
(see pages 4580–4597)
Although they may not seem related, toxic chemicals and loud acoustic noise are both environmental toxins, and exposure to one can influence vulnerability to the other. Polychlorinated biphenyls (PCBs) were banned by the Environmental Protection Agency nearly 20 years ago, but the stable chemicals remain prevalent in our surroundings. Because PCBs have access to the developing fetus in utero, prenatal exposure is common and can have consequences lasting into adulthood, including developmental deficits in hearing. This week, Ibrahim et al. explore the effects of prenatal toxin exposure in mice on risk for hearing damage later in life. Pregnant mice were exposed to PCBs (or oil only) delivered in a cookie from 28 d before breeding and throughout pregnancy, lactation, and weaning. Hearing tests showed that only male mice exhibited low-frequency hearing impairment at 3 months. In another cohort, mice were exposed to PCBs or oil prenatally and perinatally, and at age 3 months were either exposed to intense noise stimulus or received a sham treatment and were noise unexposed. Male mice that received either PCBs and/or noise exposure had higher hearing thresholds than unexposed mice, but those that received only oil displayed hearing recovery at 7 d, whereas those exposed to PCBs and noise did not recover. Previous studies have associated acoustic injury with hyperactivity in the inferior colliculus (IC), a hub for ascending auditory processing in the auditory midbrain. The researchers used two-photon in vivo microscopy to measure calcium signaling in the dorsal cortex of the IC. In mice that received PCBs and noise exposure, the researchers saw a completely disrupted tonotopic map and loss of neurons tuned to high frequencies. Neuronal responses were also blunted, and the balance of excitatory and inhibitory activity was tipped toward excitation. Together, the results demonstrate that early-life toxins can do lasting damage in both the peripheral nervous system and CNS and have nonlinear effects on resilience to future harmful experiences.
The distribution of channelrhodopsin-2-enhanced yellow fluorescent protein-positive (ChR2-EYFP+) fibers in the hippocampus.
A Novel—and Atypical—Hypothalamic–Hippocampal Circuit
Minghua Li, Jessica L. Kinney, Yu-Qiu Jiang, Daniel K. Lee, Qiwen Wu, et al.
(see pages 4612–4624)
The net effect of neuronal signaling depends not only on the nature of the presynaptic neuron—whether inhibitory or excitatory—but also on that of the postsynaptic neuron. For example, long-range communication between brain regions often relies on glutamatergic projection neurons that make en passant connections with both inhibitory interneurons and excitatory pyramidal neurons (PN), with the latter drowning out the effects of the inhibitory input. This week, though, Li et al. report a novel input from the hypothalamus to the CA3 region of the hippocampus in which selective targeting of inhibitory interneurons results in disynaptic feedforward inhibition without direct excitation of PNs. Previous studies had only looked at inputs from the hypothalamic supramammillary nucleus (SuM) to the CA2 and dentate gyrus (DG) of the hippocampus, but here the authors focused on the little-studied CA3. Retrograde viral labeling showed that neurons projected from the SuM to CA3 and made monosynaptic connections with neurons there. The authors next genetically engineered mice to express the channel rhodopsin ChR2 coupled with a fluorescent protein specifically in CA3-projecting SuM neurons and then made whole-cell electrophysiological recordings from hippocampal PNs. Not surprisingly, light-evoked EPSCs were detected in all CA2 PNs, but only a small number of blunted EPSCs were seen in CA3 neurons. In contrast, light stimulation of SuM neurons evoked large inhibitory postsynaptic currents in CA3 PNs that were blocked by glutamate receptor antagonists, suggesting that the IPSCs were driven by glutamatergic input. The IPSCs were nearly abolished by an opioid receptor agonist known to suppress inhibitory transmission by parvalbumin (PV)-expressing interneurons. Further experiments revealed that SuM neurons made robust, direct, monosynaptic connections with those inhibitory PV-expressing interneurons in the CA3, which in turn imparted a disynaptic feedforward inhibition to CA3 PNs. The work reveals a novel circuit by which hypothalamic neurons can exert direct control of hippocampal CA3—via connections with PV-expressing interneurons—independent of SuM inputs to CA2 and DG.
Footnotes
This Week in The Journal was written by Stephani Sutherland