Impaired Latent Inhibition in GDNF-Deficient Mice Exposed to Chronic Stress

Abstract

Increased reactivity to stress is maladaptive and linked to abnormal behaviors and psychopathology. Chronic unpredictable stress (CUS) alters catecholaminergic neurotransmission and remodels neuronal circuits involved in learning, attention and decision making. Glial-derived neurotrophic factor (GDNF) is essential for the physiology and survival of dopaminergic neurons in substantia nigra and of noradrenergic neurons in the locus coeruleus. Up-regulation of GDNF expression during stress is linked to resilience; on the other hand, the inability to up-regulate GDNF in response to stress, as a result of either genetic or epigenetic modifications, induces behavioral alterations. For example, GDNF-deficient mice exposed to chronic stress exhibit alterations of executive function, such as increased temporal discounting. Here we investigated the effects of CUS on latent inhibition (LI), a measure of selective attention and learning, in GDNF-heterozygous (HET) mice and their wild-type (WT) littermate controls. No differences in LI were found between GDNF HET and WT mice under baseline experimental conditions. However, following CUS, GDNF-deficient mice failed to express LI. Moreover, stressed GDNF-HET mice, but not their WT controls, showed decreased neuronal activation (number of c-Fos positive neurons) in the nucleus accumbens shell and increased activation in the nucleus accumbens core, both key regions in the expression of LI. Our results add LI to the list of behaviors affected by chronic stress and support a role for GDNF deficits in stress-induced pathological behaviors relevant to schizophrenia and other psychiatric disorders.

NrCAM-deficient mice exposed to chronic stress exhibit disrupted latent inhibition, a hallmark of schizophrenia

“…Stress mice received 21 days of CUS as in ( Dias-Ferreira et al, 2009 ; Buhusi et al, 2017a ), using the following daily randomly-chosen stressors applied at random daily times: 30 min restraint, 10 min forced swim, or 10 min exposure to an aggressive Balb/c male mouse. We have chosen this 3-week CUS protocol since stressed WT C57Bl/6 J mice seem to be resilient to this CUS ( Buhusi et al, 2016 , 2017a ), and the aim was to comparatively evaluate NrCAM-deficient mice relative to their WT littermates. It should be noted that when exposed to a longer (8-week), more complex CUS protocol ( Monteiro et al, 2015 ), C57Bl/6 J mice do show changes in anxiety, depressive-like, and exploratory behaviors.…”

“…Latent inhibition was assessed using an “on baseline” conditioned emotional response (CER) procedure consisting of baseline, pre-exposure, conditioning, rebaseline and test phases (i.e., allowing the mouse to eat during the all stages of the LI paradigm) ( Buhusi et al, 2017a , b ). Mice were assigned either to a PE tone / NPE click or PE click/NPE tone in a counterbalanced manner.…”

“…On the next day, during a 30-min test session, mice were presented with 3-min PE and NPE stimuli with an 8-min ISI (order counterbalanced between subjects). Mouse behavior was video recorded and the duration of freezing behavior was estimated using FreezeScan software (CleverSys Inc., Reston, VA) ( Buhusi et al, 2017a , b , 2023 ).…”

“…To evaluate neuronal activation, we performed c-Fos immunostaining using standard procedures ( Buhusi et al, 2016 , 2017a , b , 2023 ). Ninety min after the start of the test session mice were deeply anesthetized and transcardially perfused with a paraformaldehyde solution (4% in 0.1 M Phosphate buffer, pH 7.4).…”

GDNF/RET signaling in dopamine neurons in vivo

“…While no changes in the response to cocaine was observed in heterozygous GDNF knockout mice, these mice seem to have more immediate early gene c-Fos positive neurons in the dorsal striatum and nucleus accumbens (Airavaara et al, 2004). More recently, the heterozygous GDNF deficient mice were also suggested to have an impaired latent inhibition to chronic stress and less active (c-Fos positive) neurons in the nucleus accumbens under stress (Buhusi et al, 2017).The first 8 conditional GDNF knockout mouse in the adult DA system was made using a tamoxifen Esr1-Cre system (Hayashi and McMahon, 2002) (0.2 mg tamoxifen per day and per gram body weight intraperitoneally for four consecutive days). Surprisingly, the authors claimed an absolute requirement of GDNF for adult catecholaminergic neuron survival (Pascual et al, 2008).…”