Early life exposure to high fructose diet induces metabolic dysregulation associated with sex-specific cognitive impairment in adolescent rats.

The incidence of adolescent mental health disorders is on the rise. Epidemiological studies suggest that poor nutrition is a significant contributor to this public health crisis, specifically through exposure to high level of dietary sugar, including fructose, during critical periods of development. Previous studies have shown that elevated fructose exposure during adolescence disrupts mental health. Despite these data, it is currently unknown how fructose exposure, specifically during infancy, may impact adolescent mental health. We developed a rat experimental protocol to investigate the effects of fructose exposure during infancy on behavioral, cognitive and metabolic endpoints in adolescence. We found that exposing rats to high fructose from birth to weaning resulted in higher circulating glucose, insulin and leptin levels in adolescence. High fructose during infancy also increased bodyweight, disrupted metabolic homeostasis in the basolateral amygdala (BLA) as indicated by decreased activity of the cellular energy sensor AMPK, and impaired attention and impulsivity in a male-specific manner. This impaired attention observed in adolescent male rats following neonatal fructose exposure was partially rescued by viral-mediated, in vivo expression of a constitutively active form of AMPK in principal neurons of the BLA. Our results suggest that exposure to high level of fructose during infancy may impact adolescent mental health in a male-specific manner and that manipulation of AMPK activity may mitigate this impact.

Reward-related dynamical coupling between basolateral amygdala and nucleus accumbens.

Recognizing reward-related stimuli is crucial for survival. Neuronal projections from the basolateral amygdala (BLA) to the nucleus accumbens (NAc) play an important role in processing reward-related cues. Previous studies revealed synchronization between distant brain regions in reward-sensitive neurocircuits; however, whether the NAc synchronizes with the BLA is unknown. Here, we recorded local field potentials simultaneously from the BLA and NAc of rats during social preference tests and an appetitive conditioning test in which explicit stimuli were associated with food. BLA-NAc coherence in the theta band (5-8 Hz) increased in response to food-associated cues. Meanwhile, the modulatory strength of theta-high gamma (50-110 Hz) phase-amplitude cross-frequency coupling (PAC) in the NAc decreased. Importantly, both of these neuromodulations disappeared upon extinction. In contrast, both theta and gamma power oscillations in each region increased in the presence of social conspecifics or contexts associated with conspecifics, but coherence did not change. To potentially disrupt behavior and associated neural activity, a subgroup of rats was exposed prenatally to valproic acid (VPA), which has been shown to disrupt transcriptome and excitatory/inhibitory balance in the amygdala. VPA-exposed rats demonstrated impulsive-like behavior, but VPA did not affect BLA-NAc coherence. These findings reveal changes in BLA-NAc coherence in response to select reward-related stimuli (i.e., food-predictive cues); the differences between the tasks used here could shed light onto the functional nature of BLA-NAc coherence and are discussed.

Modulation of fear generalization by the zona incerta.

Fear expressed toward threat-associated stimuli is an adaptive behavioral response. In contrast, the generalization of fear responses toward nonthreatening cues is a maladaptive and debilitating dimension of trauma- and anxiety-related disorders. Expressing fear to appropriate stimuli and suppressing fear generalization require integration of relevant sensory information and motor output. While thalamic and subthalamic brain regions play important roles in sensorimotor integration, very little is known about the contribution of these regions to the phenomenon of fear generalization. In this study, we sought to determine whether fear generalization could be modulated by the zona incerta (ZI), a subthalamic brain region that influences sensory discrimination, defensive responses, and retrieval of fear memories. To do so, we combined differential intensity-based auditory fear conditioning protocols in mice with C-FOS immunohistochemistry and designer receptors exclusively activated by designer drugs (DREADDs)-based manipulation of neuronal activity in the ZI. C-FOS immunohistochemistry revealed an inverse relationship between ZI activation and fear generalization: The ZI was less active in animals that generalized fear. In agreement with this relationship, chemogenetic inhibition of the ZI resulted in fear generalization, while chemogenetic activation of the ZI suppressed fear generalization. Furthermore, targeted stimulation of GABAergic cells in the ZI reduced fear generalization. To conclude, our data suggest that stimulation of the ZI could be used to treat fear generalization in the context of trauma- and anxiety-related disorders.

Chronic stress induces cell type-selective transcriptomic and electrophysiological changes in the bed nucleus of the stria terminalis.

Distinct regions and cell types in the anterolateral group of the bed nucleus of the stria terminalis (BNSTALG) act to modulate anxiety in opposing ways. A history of chronic stress increases anxiety-like behavior with lasting electrophysiological effects on the BNSTALG. However, the opposing circuits within the BNSTALG suggest that stress may have differential effects on the individual cell types that comprise these circuits to shift the balance to favor anxiogenesis. Yet, the effects of stress are generally examined by treating all neurons within a particular region of the BNST as a homogenoeus population. We used patch-clamp electrophysiology and single-cell quantitative reverse transcriptase PCR (scRT-PCR) to determine how chronic shock stress (CSS) affects electrophysiological and neurochemical properties of Type I, Type II, and Type III neurons in the BNSTALG. We report that CSS resulted in changes in the input resistance, time constant, action potential waveform, and firing rate of Type III but not Type I or II neurons. Additionally, only the Type III neurons exhibited an increase in Crf mRNA and a decrease in striatal-enriched protein tyrosine phosphatase (Ptpn5) mRNA after CSS. In contrast, only non-Type III cells showed a reduction in calcium-permeable AMPA receptor (CP-AMPAR) current and changes in mRNA expression of genes encoding AMPA receptor subunits after CSS. Importantly, none of the effects of CSS observed were seen in all cell types. Our results suggest that Type III neurons play a unique role in the BNSTALG circuit and represent a population of CRF neurons particularly sensitive to chronic stress.

High-fructose diet initiated during adolescence does not affect basolateral amygdala excitability or affective-like behavior in Sprague Dawley rats.

Patients with type-2 diabetes, obesity, and metabolic syndrome have a significantly increased risk of developing depression. Dysregulated metabolism may contribute to the etiology of depression by affecting neuronal activity in key limbic areas. The basolateral amygdala (BLA) acts as a critical emotional valence detector in the brain's limbic circuit, and shows hyperactivity and abnormal glucose metabolism in depressed patients. Furthermore, administering a periadolescent high-fructose diet (HFrD; a model of metabolic syndrome) to male Wistar rats increases anxiety- and depressive-like behavior. Repeated shock stress in Sprague Dawley rats similarly increases anxiety-like behavior and increases BLA excitability. We therefore investigated whether a metabolic stressor (HFrD) would have similar effects as shock stress on BLA excitability in Sprague Dawley rats. We found that a HFrD did not affect the intrinsic excitability of BLA neurons. Fructose-fed Sprague Dawley rats had elevated body fat mass, but did not show increases in metabolic efficiency and fasting blood glucose relative to control. Finally unlike Wistar rats, fructose-fed Sprague Dawley rats did not show increased anxiety- and depressive-like behavior. These results suggest that genetic differences between rat strains may affect susceptibility to a metabolic insult. Collectively, these data show that a periadolescent HFrD disrupts metabolism, but does not change affective behavior or BLA excitability in Sprague Dawley rats.

Rho-kinase inhibition has antidepressant-like efficacy and expedites dendritic spine pruning in adolescent mice.

Adolescence represents a critical period of neurodevelopment, defined by structural and synaptic pruning within the prefrontal cortex. While characteristic of typical development, this structural instability may open a window of vulnerability to developing neuropsychiatric disorders, including depression. Thus, therapeutic interventions that support or expedite neural remodeling in adolescence may be advantageous. Here, we inhibited the neuronally-expressed cytoskeletal regulatory factor Rho-kinase (ROCK), focusing primarily on the clinically-viable ROCK inhibitor fasudil. ROCK inhibition had rapid antidepressant-like effects in adolescent mice, and its efficacy was comparable to ketamine and fluoxetine. It also modified levels of the antidepressant-related signaling factors, tropomyosin/tyrosine receptor kinase B and Akt, as well as the postsynaptic marker PSD-95, in the ventromedial prefrontal cortex (vmPFC). Meanwhile, adolescent-typical dendritic spine pruning on excitatory pyramidal neurons in the vmPFC was expedited. Further, vmPFC-specific shRNA-mediated reduction of ROCK2, the dominant ROCK isoform in the brain, had antidepressant-like consequences. We cautiously suggest that ROCK inhibitors may have therapeutic potential for adolescent-onset depression.

RDoC-based categorization of amygdala functions and its implications in autism.

Confusion endures as to the exact role of the amygdala in relation to autism. To help resolve this we turned to the NIMH's Research Domain Criteria (RDoC) which provides a classification schema that identifies different categories of behaviors that can turn pathologic in mental health disorders, e.g. autism. While RDoC incorporates all the known neurobiological substrates for each domain, this review will focus primarily on the amygdala. We first consider the amygdala from an anatomical, historical, and developmental perspective. Next, we examine the different domains and constructs of RDoC that the amygdala is involved in: Negative Valence Systems, Positive Valence Systems, Cognitive Systems, Social Processes, and Arousal and Regulatory Systems. Then the evidence for a dysfunctional amygdala in autism is presented with a focus on alterations in development, prenatal valproic acid exposure as a model for ASD, and changes in the oxytocin system therein. Finally, a synthesis of RDoC, the amygdala, and autism is offered, emphasizing the task of disambiguation and suggestions for future research.

Memory Retention Involves the Ventrolateral Orbitofrontal Cortex: Comparison with the Basolateral Amygdala.

This corrects the article DOI: 10.1038/npp.2017.139.

Repeated shock stress facilitates basolateral amygdala synaptic plasticity through decreased cAMP-specific phosphodiesterase type IV (PDE4) expression.

Previous studies have shown that exposure to stressful events can enhance fear memory and anxiety-like behavior as well as increase synaptic plasticity in the rat basolateral amygdala (BLA). We have evidence that repeated unpredictable shock stress (USS) elicits a long-lasting increase in anxiety-like behavior in rats, but the cellular mechanisms mediating this response remain unclear. Evidence from recent morphological studies suggests that alterations in the dendritic arbor or spine density of BLA principal neurons may underlie stress-induced anxiety behavior. Recently, we have shown that the induction of long-term potentiation (LTP) in BLA principal neurons is dependent on activation of postsynaptic D1 dopamine receptors and the subsequent activation of the cyclic adenosine 5'-monophosphate (cAMP)-protein kinase A (PKA) signaling cascade. Here, we have used in vitro whole-cell patch-clamp recording from BLA principal neurons to investigate the long-term consequences of USS on their morphological properties and synaptic plasticity. We provided evidence that the enhanced anxiety-like behavior in response to USS was not associated with any significant change in the morphological properties of BLA principal neurons, but was associated with a changed frequency dependence of synaptic plasticity, lowered LTP induction threshold, and reduced expression of phosphodiesterase type 4 enzymes (PDE4s). Furthermore, pharmacological inhibition of PDE4 activity with rolipram mimics the effects of chronic stress on LTP induction threshold and baseline startle. Our results provide the first evidence that stress both enhances anxiety-like behavior and facilitates synaptic plasticity in the amygdala through a common mechanism of PDE4-mediated disinhibition of cAMP-PKA signaling.

Memory Retention Involves the Ventrolateral Orbitofrontal Cortex: Comparison with the Basolateral Amygdala.

The orbitofrontal cortex (OFC) is thought to link stimuli and actions with anticipated outcomes in order to sustain flexible behavior in an ever-changing environment. How it retains these associations to guide future behavior is less well-defined. Here we focused on one subregion of this heterogeneous structure, the ventrolateral OFC (VLO). CaMKII-driven inhibitory Gi-coupled designer receptors exclusively activated by designer drugs (DREADDs) were infused and subsequently activated by their ligand Clozapine-N-oxide (CNO) in conjunction with fear extinction training (a form of aversive conditioning) and response-outcome conditioning (a form of appetitive conditioning). Gi-DREADD-mediated inactivation of the VLO during extinction conditioning interfered with fear extinction memory, resulting in sustained freezing when mice were later tested drug-free. Similarly, Gi-DREADD-mediated inactivation in conjunction with response-outcome conditioning caused a later decay in goal-directed responding-that is, mice were unable to select actions based on the likelihood that they would be rewarded in a sustainable manner. By contrast, inhibitory Gi-DREADDs in the basolateral amygdala (BLA) impaired the acquisition of both conditioned fear extinction and response-outcome conditioning, as expected based on prior studies using other inactivation techniques. Meanwhile, DREADD-mediated inhibition of the dorsolateral striatum enhanced response-outcome conditioning, also in line with prior reports. Together, our findings suggest that learning-related neuroplasticity in the VLO may be necessary for memory retention in both appetitive and aversive domains.

Serotonin gating of cortical and thalamic glutamate inputs onto principal neurons of the basolateral amygdala.

The basolateral amygdala (BLA) is a key site for crossmodal association of sensory stimuli and an important relay in the neural circuitry of emotion. Indeed, the BLA receives substantial glutamatergic inputs from multiple brain regions including the prefrontal cortex and thalamic nuclei. Modulation of glutamatergic transmission in the BLA regulates stress- and anxiety-related behaviors. Serotonin (5-HT) also plays an important role in regulating stress-related behavior through activation of both pre- and postsynaptic 5-HT receptors. Multiple 5-HT receptors are expressed in the BLA, where 5-HT has been reported to modulate glutamatergic transmission. However, the 5-HT receptor subtype mediating this effect is not yet clear. The aim of this study was to use patch-clamp recordings from BLA neurons in an ex vivo slice preparation to examine 1) the effect of 5-HT on extrinsic sensory inputs, and 2) to determine if any pathway specificity exists in 5-HT regulation of glutamatergic transmission. Two independent input pathways into the BLA were stimulated: the external capsule to mimic cortical input, and the internal capsule to mimic thalamic input. Bath application of 5-HT reversibly reduced the amplitude of evoked excitatory postsynaptic currents (eEPSCs) induced by stimulation of both pathways. The decrease was associated with an increase in the paired-pulse ratio and coefficient of variation of eEPSC amplitude, suggesting 5-HT acts presynaptically. Moreover, the effect of 5-HT in both pathways was mimicked by the selective 5-HT1B receptor agonist CP93129, but not by the 5-HT1A receptor agonist 8-OH DPAT. Similarly the effect of exogenous 5-HT was blocked by the 5-HT1B receptor antagonist GR55562, but not affected by the 5-HT1A receptor antagonist WAY 100635 or the 5-HT2 receptor antagonists pirenperone and MDL 100907. Together these data suggest 5-HT gates cortical and thalamic glutamatergic inputs into the BLA by activating presynaptic 5-HT1B receptors.

Developmental disruption of amygdala transcriptome and socioemotional behavior in rats exposed to valproic acid prenatally.

BACKGROUND: The amygdala controls socioemotional behavior and has consistently been implicated in the etiology of autism spectrum disorder (ASD). Precocious amygdala development is commonly reported in ASD youth with the degree of overgrowth positively correlated to the severity of ASD symptoms. Prenatal exposure to VPA leads to an ASD phenotype in both humans and rats and has become a commonly used tool to model the complexity of ASD symptoms in the laboratory. Here, we examined abnormalities in gene expression in the amygdala and socioemotional behavior across development in the valproic acid (VPA) rat model of ASD. METHODS: Rat dams received oral gavage of VPA (500 mg/kg) or saline daily between E11 and 13. Socioemotional behavior was tracked across development in both sexes. RNA sequencing and proteomics were performed on amygdala samples from male rats across development. RESULTS: Effects of VPA on time spent in social proximity and anxiety-like behavior were sex dependent, with social abnormalities presenting in males and heightened anxiety in females. Across time VPA stunted developmental and immune, but enhanced cellular death and disorder, pathways in the amygdala relative to saline controls. At postnatal day 10, gene pathways involved in nervous system and cellular development displayed predicted activations in prenatally exposed VPA amygdala samples. By juvenile age, however, transcriptomic and proteomic pathways displayed reductions in cellular growth and neural development. Alterations in immune pathways, calcium signaling, Rho GTPases, and protein kinase A signaling were also observed. CONCLUSIONS: As behavioral, developmental, and genomic alterations are similar to those reported in ASD, these results lend support to prenatal exposure to VPA as a useful tool for understanding how developmental insults to molecular pathways in the amygdala give rise to ASD-related syndromes.

Dynamic corticostriatal activity biases social bonding in monogamous female prairie voles.

Adult pair bonding involves dramatic changes in the perception and valuation of another individual. One key change is that partners come to reliably activate the brain's reward system, although the precise neural mechanisms by which partners become rewarding during sociosexual interactions leading to a bond remain unclear. Here we show, using a prairie vole (Microtus ochrogaster) model of social bonding, how a functional circuit from the medial prefrontal cortex to nucleus accumbens is dynamically modulated to enhance females' affiliative behaviour towards a partner. Individual variation in the strength of this functional connectivity, particularly after the first mating encounter, predicts how quickly animals begin affiliative huddling with their partner. Rhythmically activating this circuit in a social context without mating biases later preference towards a partner, indicating that this circuit's activity is not just correlated with how quickly animals become affiliative but causally accelerates it. These results provide the first dynamic view of corticostriatal activity during bond formation, revealing how social interactions can recruit brain reward systems to drive changes in affiliative behaviour.

Position and Orientation Insensitive Wireless Power Transmission for EnerCage-Homecage System.

We have developed a new headstage architecture as part of a smart experimental arena, known as the EnerCage-HC2 system, which automatically delivers stimulation and collects behavioral data over extended periods with minimal small animal subject handling or personnel intervention in a standard rodent homecage. Equipped with a four-coil inductive link, the EnerCage-HC2 system wirelessly powers the receiver (Rx) headstage, irrespective of the subject's location or head orientation, eliminating the need for tethering or carrying bulky batteries. On the transmitter (Tx) side, a driver coil, five high-quality (Q) factor segmented resonators at different heights and orientations, and a closed-loop Tx power controller create a homogeneous electromagnetic (EM) field within the homecage 3-D space, and compensate for drops in power transfer efficiency (PTE) due to Rx misalignments. The headstage is equipped with four small slanted resonators, each covering a range of head orientations with respect to the Tx resonators, which direct the EM field toward the load coil at the bottom of the headstage. Moreover, data links based on Wi-Fi, UART, and Bluetooth low energy are utilized to enables remote communication and control of the Rx. The PTE varies within 23.6%-33.3% and 6.7%-10.1% at headstage heights of 8 and 20 cm, respectively, while continuously delivering >40 mW to the Rx electronics even at 90° rotation. As a proof of EnerCage-HC2 functionality in vivo, a previously documented on-demand electrical stimulation of the globus pallidus, eliciting consistent head rotation, is demonstrated in three freely behaving rats.

A comparative analysis of the physiological properties of neurons in the anterolateral bed nucleus of the stria terminalis in the Mus musculus, Rattus norvegicus, and Macaca mulatta.

The anterolateral group of the bed nucleus of the stria terminalis (BNSTALG ) is a critical modulator of a variety of rodent and primate behaviors spanning anxiety behavior and drug addiction. Three distinct neuronal cell types have been previously defined in the rat BNSTALG based on differences in the voltage-response to hyperpolarizing and depolarizing current injection. Differences in genetic expression profile between these three cell types suggest electrophysiological cell type may be an indicator for functional differences in the circuit of the rat BNSTALG . Although the behavioral role of the BNST is conserved across species, it is unknown if the same electrophysiological cell types exist in the BNSTALG of the mouse and nonhuman primate. Here, we used whole-cell patch clamp electrophysiology and neuronal reconstructions of biocytin-filled neurons to compare and contrast the electrophysiological and morphological properties of neurons in the BNSTALG from the mouse, rat, and rhesus macaque. We provide evidence that the BNSTALG of all three species contains neurons that match the three defined cell types found in the rat; however, there are intriguing differences in the relative frequency of these cell types as well as electrophysiological and morphological properties of the BNSTALG neurons across species. This study suggests that the overall landscape of the BNSTALG in the primate and mouse may be similar to that of the rat in some aspects but perhaps significantly different in others.

Connections of the Mouse Orbitofrontal Cortex and Regulation of Goal-Directed Action Selection by Brain-Derived Neurotrophic Factor.

BACKGROUND: Distinguishing between actions that are more likely or less likely to be rewarded is a critical aspect of goal-directed decision making. However, neuroanatomic and molecular mechanisms are not fully understood. METHODS: We used anterograde tracing, viral-mediated gene silencing, functional disconnection strategies, pharmacologic rescue, and designer receptors exclusively activated by designer drugs (DREADDs) to determine the anatomic and functional connectivity between the orbitofrontal cortex (OFC) and the amygdala in mice. In particular, we knocked down brain-derived neurotrophic factor (Bdnf) bilaterally in the OFC or generated an OFC-amygdala "disconnection" by pairing unilateral OFC Bdnf knockdown with lesions of the contralateral amygdala. We characterized decision-making strategies using a task in which mice selected actions based on the likelihood that they would be reinforced. Additionally, we assessed the effects of DREADD-mediated OFC inhibition on the consolidation of action-outcome conditioning. RESULTS: As in other species, the OFC projects to the basolateral amygdala and dorsal striatum in mice. Bilateral Bdnf knockdown within the ventrolateral OFC and unilateral Bdnf knockdown accompanied by lesions of the contralateral amygdala impede goal-directed response selection, implicating BDNF-expressing OFC projection neurons in selecting actions based on their consequences. The tyrosine receptor kinase B agonist 7,8-dihydroxyflavone rescues action selection and increases dendritic spine density on excitatory neurons in the OFC. Rho-kinase inhibition also rescues goal-directed response strategies, linking neural remodeling with outcome-based decision making. Finally, DREADD-mediated OFC inhibition weakens new action-outcome memory. CONCLUSIONS: Activity-dependent and BDNF-dependent neuroplasticity within the OFC coordinate outcome-based decision making through interactions with the amygdala. These interactions break reward-seeking habits, a putative factor in multiple psychopathologies.

Molecular characterization of Thy1 expressing fear-inhibiting neurons within the basolateral amygdala.

Molecular characterization of neuron populations, particularly those controlling threat responses, is essential for understanding the cellular basis of behaviour and identifying pharmacological agents acting selectively on fear-controlling circuitry. Here we demonstrate a comprehensive workflow for identification of pharmacologically tractable markers of behaviourally characterized cell populations. Thy1-eNpHR-, Thy1-Cre- and Thy1-eYFP-labelled neurons of the BLA consistently act as fear inhibiting or 'Fear-Off' neurons during behaviour. We use cell-type-specific optogenetics and chemogenetics (DREADDs) to modulate activity in this population during behaviour to block or enhance fear extinction. Dissociated Thy1-eYFP neurons are isolated using FACS. RNA sequencing identifies genes strongly upregulated in RNA of this population, including Ntsr2, Dkk3, Rspo2 and Wnt7a. Pharmacological manipulation of neurotensin receptor 2 confirms behavioural effects observed in optogenetic and chemogenetic experiments. These experiments identify and validate Ntsr2-expressing neurons within the BLA, as a putative 'Fear-Off' population.

Amygdala-Dependent Molecular Mechanisms of the Tac2 Pathway in Fear Learning.

Recently we determined that activation of the tachykinin 2 (Tac2) pathway in the central amygdala (CeA) is necessary and sufficient for the modulation of fear memories. The Tac2 pathway includes the Tac2 gene, which encodes the neuropeptide neurokinin B and its corresponding receptor neurokinin 3 receptor (NK3R). In this study, using Tac2-cre and Tac2-GFP mice, we applied a combination of in vivo (optogenetics) and multiple in vitro techniques to further explore the mechanisms of action within the Tac2 pathway. In transgenic mice that express ChR2 solely in Tac2 neurons, in vivo optogenetic stimulation of CeA Tac2-expressing neurons during fear acquisition enhanced fear memory consolidation and drove action potential firing in vitro. In addition, Tac2-CeA neurons were shown to co-express striatal-enriched protein tyrosine phosphatase, which may have an important role in regulating Nk3R signaling during fear conditioning. These data extend our current understanding for the underlying mechanism(s) for the role of the Tac2 pathway in the regulation of fear memory, which may serve as a new therapeutic target in the treatment of fear-related disorders.

Morphology and dendritic maturation of developing principal neurons in the rat basolateral amygdala.

The basolateral nucleus of the amygdala (BLA) assigns emotional valence to sensory stimuli, and many amygdala-dependent behaviors undergo marked development during postnatal life. We recently showed principal neurons in the rat BLA undergo dramatic changes to their electrophysiological properties during the first postnatal month, but no study to date has thoroughly characterized changes to morphology or gene expression that may underlie the functional development of this neuronal population. We addressed this knowledge gap with reconstructions of biocytin-filled principal neurons in the rat BLA at postnatal days 7 (P7), 14, 21, 28, and 60. BLA principal neurons underwent a number of morphological changes, including a twofold increase in soma volume from P7 to P21. Dendritic arbors expanded significantly during the first postnatal month and achieved a mature distribution around P28, in terms of total dendritic length and distance from soma. The number of primary dendrites and branch points were consistent with age, but branch points were found farther from the soma in older animals. Dendrites of BLA principal neurons at P7 had few spines, and spine density increased nearly fivefold by P21. Given the concurrent increase in dendritic material, P60 neurons had approximately 17 times as many total spines as P7 neurons. Together, these developmental transitions in BLA principal neuron morphology help explain a number of concomitant electrophysiological changes during a critical period in amygdala development.

Oxytocin in the nucleus accumbens shell reverses CRFR2-evoked passive stress-coping after partner loss in monogamous male prairie voles.

Loss of a partner can have severe effects on mental health. Here we explore the neural mechanisms underlying increased passive stress-coping, indicative of depressive-like behavior, following the loss of the female partner in the monogamous male prairie vole. We demonstrate that corticotropin-releasing factor receptor 2 (CRFR2) in the nucleus accumbens shell mediates social loss-induced passive coping. Further, we show that partner loss compromises the oxytocin system through multiple mechanisms. Finally, we provide evidence for an interaction of the CRFR2 and oxytocin systems in mediating the emotional consequences of partner loss. Our results suggest that chronic activation of CRFR2 and suppression of striatal oxytocin signaling following partner loss result in an aversive emotional state that may share underlying mechanisms with bereavement. We propose that the suppression of oxytocin signaling is likely adaptive during short separations to encourage reunion with the partner and may have evolved to maintain long-term partnerships. Additionally, therapeutic strategies targeting these systems should be considered for treatment of social loss-mediated depression.