Abstract
Adverse experiences by the developing fetus and in early childhood are associated with profound effects on learning, emotional behavior, and cognition as a whole. In this study we investigated the effects of prenatal nicotine exposure (NIC), postnatal maternal deprivation (MD) or the combination of the two (NIC+MD) to determine if hippocampal neuron development is modulated by exposure to drugs of abuse and/or stress. Growth of rat offspring exposed to MD alone or NIC+MD was repressed until after weaning. In CA1 but not CA3 of postnatal day 14 (P14) pups, MD increased pyramidal neurons, however, in dentate gyrus (DG), decreased granule neurons. NIC had no effect on neuron number in CA1, CA3 or DG. Unexpectedly, NIC plus MD combined caused a synergistic increase in the number of CA1 or CA3 neurons. Neuron density in CA regions was unaffected by treatment, but in the DG, granule neurons had a looser packing density after NIC, MD or NIC+MD exposure. When septotemporal axes were analyzed, the synergism of stress and drug exposure in CA1 and CA3 was associated with rostral, whereas MD effects were predominantly associated with caudal neurons. TUNEL labeling suggests no active apoptosis at P14, and doublecortin positive neurons and mossy fibers were diminished in NIC+MD relative to controls. The laterality of the effect of nicotine and/or maternal deprivation in right versus left hippocampus was also analyzed and found to be insiginificant. We report for the first time that early life stressors such as postnatal MD and prenatal NIC exposure, when combined, may exhibit synergistic consequences for CA1 and CA3 pyramidal neuron development, and a potential antagonistic influence on developing DG neurons. These results suggest that early stressors may modulate neurogenesis, apoptosis, or maturation of glutamatergic neurons in the hippocampus in a region-specific manner during critical periods of neurodevelopment.
Highlights
The experience of trauma, abuse, or neglect during infancy, puts individuals at risk for developing psychiatric diseases such as major depression, anxiety, hyperactivity, and posttraumatic stress disorder (PTSD) [1,2,3,4,5], and can be a trigger for schizophrenia and borderline personality disorders later in life [2,4,5]
Our findings show that developing CA1 was sensitive to developmental perturbations, and this sensitivity resulted in increased pyramidal neuron numbers at postnatal day 14 (P14), whereas developing dentate gyrus (DG) was primarily sensitive to the maternal deprivation (MD) treatment, which resulted in decreased neuron numbers
The novel findings reported in this study provide evidence of a greater than additive effect of maternal deprivation combined with prenatal nicotine exposure in CA1 and CA3 at P14, and these synergistic effects can be attributed to the rostral hippocampus
Summary
The experience of trauma, abuse, or neglect during infancy, puts individuals at risk for developing psychiatric diseases such as major depression, anxiety, hyperactivity, and posttraumatic stress disorder (PTSD) [1,2,3,4,5], and can be a trigger for schizophrenia and borderline personality disorders later in life [2,4,5] Experience of these early life stressors is associated with increased risk for substance abuse, including heavy nicotine use [6,7], a common behavior in patients who suffer from major depression, schizophrenia, and anxiety. Perturbation of neuronal development by exposure to drug or stressful situations is likely to disturb the expansion of neural progenitor cells, possibly by interfering with proliferation, migration and maturation of neurons, and may affect the pruning of cell numbers via apoptosis
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