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1.
Neuropharmacology ; 150: 153-163, 2019 05 15.
Article in English | MEDLINE | ID: mdl-30926450

ABSTRACT

Accumulating evidence indicates that exposure to general anesthetics during infancy and childhood can cause persistent cognitive impairment, alterations in synaptic plasticity, and, to a lesser extent, increased incidence of behavioral disorders. Unfortunately, the developmental parameters of susceptibility to general anesthetics are not well understood. Adolescence is a critical developmental period wherein multiple late developing brain regions may also be vulnerable to enduring general anesthetic effects. Given the breadth of the adolescent age span, this group potentially represents millions more individuals than those exposed during early childhood. In this study, isoflurane exposure within a well-characterized adolescent period in Sprague-Dawley rats elicited immediate and persistent anxiety- and impulsive-like responding, as well as delayed cognitive impairment into adulthood. These behavioral abnormalities were paralleled by atypical dendritic spine morphology in the prefrontal cortex (PFC) and hippocampus (HPC), suggesting delayed anatomical maturation, and shifts in inhibitory function that suggest hypermaturation of extrasynaptic GABAA receptor inhibition. Preventing this hypermaturation of extrasynaptic GABAA receptor-mediated function in the PFC selectively reversed enhanced impulsivity resulting from adolescent isoflurane exposure. Taken together, these data demonstrate that the developmental window for susceptibility to enduring untoward effects of general anesthetics may be much longer than previously appreciated, and those effects may include affective behaviors in addition to cognition.


Subject(s)
Affect/drug effects , Anesthetics, General/pharmacology , Behavior, Animal/drug effects , Cognition/drug effects , Isoflurane/pharmacology , Neuronal Plasticity/drug effects , Animals , Dendritic Spines/drug effects , Exploratory Behavior/drug effects , Impulsive Behavior/drug effects , Male , Prefrontal Cortex/drug effects , Pyramidal Cells/drug effects , Rats , Rats, Sprague-Dawley
3.
Neuroscience ; 361: 129-143, 2017 Oct 11.
Article in English | MEDLINE | ID: mdl-28807788

ABSTRACT

Adolescence has been identified as a vulnerable developmental time period during which exposure to drugs can have long-lasting, detrimental effects. Although adolescent binge-like ethanol (EtOH) exposure leads to a significant reduction in forebrain cholinergic neurons, EtOH's functional effect on acetylcholine (ACh) release during behavior has yet to be examined. Using an adolescent intermittent ethanol exposure model (AIE), rats were exposed to binge-like levels of EtOH from postnatal days (PD) 25 to 55. Three weeks following the final EtOH exposure, cholinergic functioning was assessed during a spontaneous alternation protocol. During maze testing, ACh levels increased in both the hippocampus and prefrontal cortex. However, selectively in the prefrontal cortex, AIE rats displayed reduced levels of behaviorally relevant ACh efflux. We found no treatment differences in spatial exploration, spatial learning, spatial reversal, or novel object recognition. In contrast, AIE rats were impaired during the first attentional set shift on an operant set-shifting task, indicative of an EtOH-mediated deficit in cognitive flexibility. A unique pattern of cholinergic cell loss was observed in the basal forebrain following AIE: Within the medial septum/diagonal band there was a selective loss (30%) of choline acetyltransferase (ChAT)-positive neurons that were nestin negative (ChAT+/nestin-); whereas in the Nucleus basalis of Meynert (NbM) there was a selective reduction (50%) in ChAT+/nestin+. These results indicate that early adolescent binge EtOH exposure leads to a long-lasting frontocortical functional cholinergic deficit, driven by a loss of ChAT+/nestin+ neurons in the NbM, which was associated with impaired cognitive flexibility during adulthood.


Subject(s)
Cholinergic Neurons/drug effects , Ethanol/pharmacology , Hippocampus/drug effects , Prosencephalon/drug effects , Acetylcholine/pharmacology , Aging , Animals , Basal Forebrain/drug effects , Basal Forebrain/metabolism , Basal Nucleus of Meynert/drug effects , Basal Nucleus of Meynert/metabolism , Choline O-Acetyltransferase/metabolism , Cholinergic Neurons/metabolism , Hippocampus/metabolism , Male , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Prosencephalon/metabolism , Rats, Sprague-Dawley
4.
Neuroscience ; 348: 324-334, 2017 04 21.
Article in English | MEDLINE | ID: mdl-28257889

ABSTRACT

Chronic intermittent exposure to ethanol (EtOH; CIE) that produces binge-like levels of intoxication has been associated with age-dependent deficits in cognitive functioning. Male Sprague-Dawley rats were exposed to CIE (5g/kg, 25% EtOH, 13 intragastric gavages) beginning at three ages: early adolescence (postnatal day [PD] 28), mid-adolescence (PD35) and adulthood (PD72). In experiment 1, rats were behaviorally tested following CIE. Spatial memory was not affected by CIE, but adult CIE rats were impaired at acquiring a non-spatial discrimination task and subsequent reversal tasks. Rats exposed to CIE during early or mid-adolescence were impaired on the first reversal, demonstrating transient impairment in behavioral flexibility. Blood EtOH concentrations negatively correlated with performance on reversal tasks. Experiment 2 examined changes in brain-derived neurotrophic factor (BDNF) levels within the frontal cortex (FC) and hippocampus (HPC) at four time points: during intoxication, 24 h after the final EtOH exposure (acute abstinence), 3 weeks following abstinence (recovery) and after behavioral testing. HPC BDNF levels were not affected by CIE at any time point. During intoxication, BDNF was suppressed in the FC, regardless of the age of exposure. However, during acute abstinence, reduced FC BDNF levels persisted in early adolescent CIE rats, whereas adult CIE rats displayed an increase in BDNF levels. Following recovery, neurotrophin levels in all CIE rats recovered. Our results indicate that intermittent binge-like EtOH exposure leads to acute disruptions in FC BDNF levels and long-lasting behavioral deficits. However, the type of cognitive impairment and its duration differ depending on the age of exposure.


Subject(s)
Behavior, Animal/drug effects , Brain-Derived Neurotrophic Factor/metabolism , Ethanol/administration & dosage , Frontal Lobe/drug effects , Age Factors , Animals , Discrimination Learning/drug effects , Frontal Lobe/metabolism , Hippocampus/drug effects , Hippocampus/metabolism , Rats , Rats, Sprague-Dawley , Reversal Learning/drug effects
5.
PLoS One ; 11(3): e0149987, 2016.
Article in English | MEDLINE | ID: mdl-26930631

ABSTRACT

Previous research has found that adolescent ethanol (EtOH) exposure alters drug seeking behaviors, cognition and neuroplasticity. Using male Sprague Dawley rats, differences in spatial working memory, non-spatial discrimination learning and behavioral flexibility were explored as a function of age at the onset (mid-adolescent vs. adult) of chronic EtOH exposure (CET). Concentrations of mature brain-derived neurotrophic factor (mBDNF) and beta-nerve growth factor (ß-NGF) in the prefrontal cortex and hippocampus were also assessed at different time-points: during CET, following acute abstinence (48-hrs), and after protracted abstinence (6-8 wks). Our results revealed that an adolescent onset of CET leads to increased EtOH consumption that persisted into adulthood. In both adult and adolescent onset CET groups, there were significant long-term reductions in prefrontal cortical mBDNF and ß-NGF levels. However, only adult onset CET rats displayed decreased hippocampal BDNF levels. Spatial memory, assessed by spontaneous alternation and delayed alternation, was not significantly affected by CET as a function of age of drinking onset, but higher blood-EtOH levels were correlated with lower spontaneous alternation scores. Regardless of the age of onset, EtOH exposed rats were impaired on non-spatial discrimination learning and displayed inflexible behavioral patterns upon reversal learning. Our results indicate that adolescent EtOH exposure changes long-term consumption patterns producing behavioral and neural dysfunctions that persist across the lifespan.


Subject(s)
Alcohol Drinking , Behavior, Animal/drug effects , Ethanol/pharmacology , Nerve Growth Factors/metabolism , Age Factors , Animals , Behavior, Animal/physiology , Brain-Derived Neurotrophic Factor/metabolism , Central Nervous System Depressants/pharmacology , Ethanol/administration & dosage , Hippocampus/drug effects , Hippocampus/metabolism , Male , Prefrontal Cortex/drug effects , Prefrontal Cortex/metabolism , Rats, Sprague-Dawley , Spatial Learning/drug effects , Spatial Learning/physiology , Time Factors , Weight Gain/drug effects , Weight Gain/physiology
6.
Brain Topogr ; 26(3): 468-78, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23322210

ABSTRACT

A key question in neuroscience is how memory is selectively allocated to neural networks in the brain. This question remains a significant research challenge, in both rodent models and humans alike, because of the inherent difficulty in tracking and deciphering large, highly dimensional neuronal ensembles that support memory (i.e., the engram). In a previous study we showed that consolidation of a new fear memory is allocated to a common topography of amygdala neurons. When a consolidated memory is retrieved, it may enter a labile state, requiring reconsolidation for it to persist. What is not known is whether the original spatial allocation of a consolidated memory changes during reconsolidation. Knowledge about the spatial allocation of a memory, during consolidation and reconsolidation, provides fundamental insight into its core physical structure (i.e., the engram). Using design-based stereology, we operationally define reconsolidation by showing a nearly identical quantity of neurons in the dorsolateral amygdala (LAd) that expressed a plasticity-related protein, phosphorylated mitogen-activated protein kinase, following both memory acquisition and retrieval. Next, we confirm that Pavlovian fear conditioning recruits a stable, topographically organized population of activated neurons in the LAd. When the stored fear memory was briefly reactivated in the presence of the relevant conditioned stimulus, a similar topography of activated neurons was uncovered. In addition, we found evidence for activated neurons allocated to new regions of the LAd. These findings provide the first insight into the spatial allocation of a fear engram in the LAd, during its consolidation and reconsolidation phase.


Subject(s)
Amygdala/cytology , Brain Mapping , Conditioning, Psychological , Fear , Memory/physiology , Neurons/physiology , Acoustic Stimulation/adverse effects , Analysis of Variance , Animals , Freezing Reaction, Cataleptic/physiology , Image Processing, Computer-Assisted , Male , Mitogen-Activated Protein Kinase Kinases/blood , Rats , Rats, Sprague-Dawley
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