Younglim Lee

A Primary Acoustic Startle Pathway: Obligatory Role of Cochlear Root Neurons and the Nucleus Reticularis Pontis Caudalis

Davis et al. (1982) proposed a primary acoustic startle circuit in rats consisting of the auditory nerve, posteroventral cochlear nucleus, an area near the ventrolateral lemniscus (VLL), nucleus reticularis pontis caudalis (PnC), and spinal motoneurons. Using fiber-sparing lesions, the present study reevaluated these and other structures together with the role of neurons embedded in the auditory nerve [cochlear root neurons (CRNs)], recently hypothesized to be involved in acoustic startle. Small electrolytic lesions of the VLL or ventrolateral tegmental nucleus (VLTg) failed to eliminate startle. Large electrolytic lesions including the rostral ventral nucleus of the trapezoid body (rVNTB) and ventrolateral parts of PnC or lesions of the entire PnC blocked startle. However, small NMDA-induced lesions of the rVNTB failed to block startle, making it unlikely that the rVNTB itself is part of the startle pathway. In contrast, NMDA lesions of the full extension of the ventrolateral part of the PnC blocked startle completely, suggesting that the ventrolateral part of the PnC is critically involved. Bilateral kainic acid lesions of CRNs also blocked the startle reflex completely, providing the first direct evidence for an involvement of CRNs in startle. This blockade probably was not caused by damage to the auditory nerve, because the lesioned animals showed intact compound action potentials recorded from the ventral cochlear nucleus. Hence, a primary acoustic startle pathway may involve three synapses onto (1) CRNs, (2) neurons in PnC, and (3) spinal motoneurons.

Roles of the Amygdala and Bed Nucleus of the Stria Terminalis in Fear and Anxiety Measured with the Acoustic Startle Reflex

Over the last several years, our laboratory has been studying how a simple reflex, the acoustic startle reflex, can be modified by prior emotional learning. Thus far, most of our work has concentrated on an experimental paradigm called the fearpotentiated startle effect, in which the amplitude of the startle reflex can be modified by a state of fear. More recently, however, we are trying to develop experimental methods to measure both fear and anxiety using changes in the acoustic startle reflex. Fear is a natural, adaptive change in an organism elicited by a potentially threatening stimulus which prepares the organism to cope with the provocation. Fear generally is elicited by a clearly identifiable stimulus and subsides shortly after its offset. Anxiety also is a change in the state of an organism which has many of the same signs and symptoms of fear. However, it may not be clearly associated with a single eliciting stimulus, may last a long time once activated, and may lack clear adaptive significance.

Glutamatergic (N-Methyl-d-aspartate Receptor) Hypofrontality in Schizophrenia: Too Little Juice or a Miswired Brain?

Dopamine D2 receptor blockade has been an obligate mechanism of action present in all medications that effectively treat positive symptoms of schizophrenia (e.g., delusions and hallucinations) and have been approved by regulatory agencies since the 1950s. Blockade of 5-hydroxytrypatmine2A receptors plays a contributory role in the actions of the second generation of antipsychotic drugs, the so-called atypical antipsychotics. Nevertheless, substantial unmet medical needs remain for the treatment of negative symptoms and cognitive dysfunction. Recognition that dissociative anesthetics block the N-methyl-d-aspartate (NMDA) receptor channel has inspired a search for glutamatergic therapeutic mechanisms because ketamine and phencyclidine are known to induce psychotic-like symptoms in healthy volunteers and exacerbate the symptoms of patients with schizophrenia. Current pathophysiological theories of schizophrenia emphasize that hypofunction of NMDA receptors at critical sites in local circuits modulate the function of a given brain region or control projections from one region to another (e.g., hippocampal-cortical or thalamocortical projections). The demonstration that a metabotropic glutamate 2/3 (mGlu2/3) receptor agonist prodrug decreased both positive and negative symptoms of schizophrenia raised hopes that glutamatergic mechanisms may provide therapeutic advantages. In addition to discussing the activation of mGlu2 receptors with mGlu2/3 receptor agonists or mGlu2 receptor positive allosteric modulators (PAMs), we discuss other methods that may potentially modulate circuits with hypofunctional NMDA receptors such as glycine transporter inhibitors and mGlu5 receptor PAMs. The hope is that by modulating glutamatergic neurotransmission, the dysfunctional circuitry of the schizophrenic brain (both local circuits and long-loop pathways) will be improved.

Effect of corticosterone on the enhancement of the acoustic startle reflex by corticotropin releasing factor (CRF)

The present study evaluated the effects of adrenalectomy and chronic administration of corticosterone on the ability of CRF given intraventricularly to increase the amplitude of the acoustic startle reflex in rats. Experiment 1 showed that CRF-enhanced startle was not affected by adrenalectomy, indicating a central effect independent of the integrity of the hypothalamic-pituitary-adrenal axis. In Experiment 2, chronic injection of corticosterone augmented CRF-enhanced startle using a dose of CRF (0.25 micrograms) that normally is ineffective in increasing startle amplitude. Chronic injection of corticosterone by itself did not increase startle amplitude (Experiment 3). We suggest that the potentiation of CRF-enhanced startle by corticosterone may result from an activation of CRF in the central nucleus of the amygdala.

Lack of a temporal gradient of retrograde amnesia following NMDA-induced lesions of the basolateral amygdala assessed with the fear-potentiated startle paradigm.

M. Kim and M. Davis (1993b) previously reported that electrolytic lesions of the central nucleus of the amygdala, made 6 or 30 days after training, completely blocked the expression of fear-potentiated startle in rats. The present study shows that excitotoxic lesions of the basolateral amygdala also block fear-potentiated startle and do so whether the lesions are made soon (i.e., 6 days) or long (i.e., 30 days) after training. The relevance of these findings to various theories of amygdala function is discussed.

Opposing roles of the amygdala and dorsolateral periaqueductal gray in fear-potentiated startle.

The whole-body acoustic startle response is a short-latency reflex mediated by a relatively simple neural circuit in the lower brainstem and spinal cord. The amplitude of this reflex is markedly enhanced by moderate fear levels, and less effectively increased by higher fear levels. Extensive evidence indicates that the amygdala plays a key role in the potentiation of startle by moderate fear. More recent evidence suggests that the periaqueductal gray is involved in the loss of potentiated startle at higher levels of fear. The influence of both structures may be mediated by anatomical connections with the acoustic startle circuit, perhaps at the level of the nucleus reticularis pontis caudalis. The present chapter reviews these data.

Role of corticotropin-releasing factor receptor-1 in opiate withdrawal.

Abstract: Previous studies indicate that corticotropin‐releasing factor (CRF) contributes to the anxiety‐like and aversive states associated with drug‐induced withdrawal. The present study extends this work by analyzing the CRF receptor subtype involved in withdrawal responses. First, the influence of a selective CRF receptor‐1 (CRF‐R1) antagonist, CP‐154,526, on opiate withdrawal behavior was examined. Pretreatment with the CRF‐R1 antagonist significantly attenuated several behavioral signs of naltrexone‐induced morphine withdrawal, including writhing, chewing, weight loss, lacrimation, salivation, and irritability, measured during the first hour of withdrawal. Next the expression of CRF‐R1 was determined as a second measure of the involvement of this receptor in opiate withdrawal. Naltrexone‐induced morphine withdrawal resulted in down‐regulation of CRF‐R1 mRNA in several brain regions, including the frontal cortex, parietal cortex, striatum, nucleus accumbens, and amygdala, but not in the hypothalamus or periaqueductal gray. Expression of CRF‐R2, the other major CRF receptor subtype, was not down‐regulated significantly by withdrawal in any of the regions examined, although morphine alone significantly increased levels of this receptor subtype. Taken together, the behavioral and receptor regulation findings indicate that CRF‐R1 is the primary mediator of the actions of the CRF system on opiate withdrawal, although it is possible that CRF‐R2 contributes to the response.

Default-Mode-Like Network Activation in Awake Rodents

During wakefulness and in absence of performing tasks or sensory processing, the default-mode network (DMN), an intrinsic central nervous system (CNS) network, is in an active state. Non-human primate and human CNS imaging studies have identified the DMN in these two species. Clinical imaging studies have shown that the pattern of activity within the DMN is often modulated in various disease states (e.g., Alzheimers, schizophrenia or chronic pain). However, whether the DMN exists in awake rodents has not been characterized. The current data provides evidence that awake rodents also possess ‘DMN-like’ functional connectivity, but only subsequent to habituation to what is initially a novel magnetic resonance imaging (MRI) environment as well as physical restraint. Specifically, the habituation process spanned across four separate scanning sessions (Day 2, 4, 6 and 8). At Day 8, significant (p<0.05) functional connectivity was observed amongst structures such as the anterior cingulate (seed region), retrosplenial, parietal, and hippocampal cortices. Prior to habituation (Day 2), functional connectivity was only detected (p<0.05) amongst CNS structures known to mediate anxiety (i.e., anterior cingulate (seed region), posterior hypothalamic area, amygdala and parabracial nucleus). In relating functional connectivity between cingulate-default-mode and cingulate-anxiety structures across Days 2-8, a significant inverse relationship (r = −0.65, p = 0.0004) was observed between these two functional interactions such that increased cingulate-DMN connectivity corresponded to decreased cingulate anxiety network connectivity. This investigation demonstrates that the cingulate is an important component of both the rodent DMN-like and anxiety networks.

Role of the Septum in the Excitatory Effect of Corticotropin-Releasing Hormone on the Acoustic Startle Reflex

Intracerebroventricular administration of corticotropin-releasing hormone (CRH) elicits a constellation of behavioral, autonomic, and endocrinological changes typically observed in stress. One of the behavioral changes after intracerebroventricular CRH is a profound increase of startle amplitude (CRH-enhanced startle). The present study examined the role of the septum in CRH-enhanced startle. The septum has direct and indirect connections to the amygdala and inhibits the amygdala. Electrophysiological data show that CRH in the septum is inhibitory. Therefore, it has been hypothesized that intracerebroventricular CRH inhibits the septum, which in turn disinhibits the amygdala, resulting in a constellation of changes via activation of amygdala efferent targets. In testing this hypothesis, it was found that electrolytic lesions of the medial septum, but not the lateral septum, blocked CRH-enhanced startle. However, fiber-sparing chemical lesions of the medial septum did not block CRH-enhanced startle, suggesting that the blockade seen with the electrolytic lesions was caused by damage to fibers of passage. A major fiber bundle passing through the medial septum is the fornix, the primary efferent pathway for the hippocampus. Fimbria transection blocked CRH-enhanced startle almost completely, whereas the large electrolytic lesions of the dorsal hippocampus did not block CRH-enhanced startle. Taken together, these data suggest that perhaps the ventral hippocampus and its efferent target areas, which communicate via the fimbria, may be critically involved in CRH-enhanced startle.

The mGlu2/3 receptor agonist LY354740 suppresses immobilization stress-induced increase in rat prefrontal cortical BDNF mRNA expression.

Both a 5-hydroxytryptamine2A (5-HT2A) agonist and immobilization stress previously have been shown to differentially alter brain-derived neurotrophic factor (BDNF) mRNA expression in the neocortex and hippocampus. Both 5-HT2A receptor activation and immobilization stress also increase glutamate release in the rat prefrontal cortex. Given that the metabotropic glutamate2/3 receptor (mGluR2/3) agonist (1S,2S,5R,6S)-2-aminobicyclo[3.1.0] hexane-2,6-dicarboxylate monohydrate (LY354740) suppressed electrophysiological, behavioral and biochemical effects of 5-HT2A receptor activation in the medial prefrontal cortex (mPFC), we assessed the efficacy of the mGluR2/3 agonist in suppressing the stress-induced increase in BDNF mRNA expression. LY35740 (10 mg/kg, i.p.) attenuated the immobilization stress-induced increase in BDNF mRNA expression in the rat mPFC. This result is consistent with the hypothesis that mGlu2/3 agonists may be an efficacious treatment for stress-induced neuropsychiatric syndromes.