Memory dysfunction is a symptomatic feature of many neurologic and neuropsychiatric disorders; however, the basic underlying mechanisms of memory and altered states of circuitry function associated with disorders of memory remain a vast unexplored territory.
The initial discovery of endogenous neurosteroids triggered a quest to elucidate their role as neuromodulators in normal and diseased brain function
In this review, based on the perspective of our own research, the advances leading to the discovery of positive and negative neurosteroid allosteric modulators of GABA type-A (GABAA), NMDA, and non-NMDA type glutamate receptors are brought together in a historical and conceptual framework
We extend the analysis toward a state-of-the art view of how neurosteroid modulation of neural circuitry function may affect memory and memory deficits.
By aggregating the results from multiple laboratories using both animal models for disease and human clinical research on neuropsychiatric and age-related neurodegenerative disorders, elements of a circuitry level view begins to emerge.
Lastly, the effects of both endogenously active and exogenously administered neurosteroids on neural networks across the life span of women and men point to a possible underlying pharmacological connectome by which these neuromodulators might act to modulate memory across diverse altered states of mind.
Unexpectedly, we also found that pregnenolone sulfate (PregS), a novel negatively charged steroid derived from the sulfation of pregnenolone (PREG), potentiated N-methyl-D-aspartate receptor (NMDAR) function (24) (Figure 1 and Table 1).
Lipophilic steroid hormones, such as progesterone, estradiol and testosterone cross the BBB and readily gain access to the CNS (5) where they can serve as agonists of steroid hormone receptors that in turn act at genomic response elements
In the early 1980s, several lines of evidence from Etienne, Baulieu, and Robel (6–9) challenged the central dogma that neuroactive steroids were exclusively synthesized peripherally, demonstrating for the first time that steroids could be synthesized from cholesterol within the CNS.
Such steroids were called neurosteroids
the research of Selye (10) showing that steroids could have anesthetic effects. Four decades later, in 1983, radiolabeling studies by Sapolsky, McEwen, and Rainbow revealed uptake of corticosterone in the stratum oriens and apical dendrite regions of the hippocampus, suggesting that GABAergic interneurons in these regions might possess corticosterone receptors
Corticosterone treatment had been shown to affect GABA uptake in the hippocampus, possibly suggesting a mechanism for hormonal modulation of memory
Subsequent research by multiple investigators demonstrated that several reduced metabolites of progesterone and deoxycorticosterone act as positive allosteric modulators of GABAARs (13–17), much like benzodiazepines (18, 19). Other research (20, 21) also suggested that neurosteroids might be capable of modulating inhibitory GABAergic neurotransmission.
the early work of Fong-sen Wu and Terrell Gibbs in my lab (23) showing that progesterone did in fact modulate GABAA and glycine receptors. Unexpectedly, we also found that pregnenolone sulfate (PregS), a novel negatively charged steroid derived from the sulfation of pregnenolone (PREG), potentiated N-methyl-D-aspartate receptor (NMDAR) function
Over the ensuing 25 years, endogenous neurosteroids have been implicated in learning and memory function, hippocampal information processes, and synaptic plasticity
Neurosteroids have also been implicated in the etiology and treatment of learning and memory disturbances associated with certain neuropsychiatric disorders, including schizophrenia, depression, and anxiety
This review summarizes the field from the perspective of our own research, which has spanned the past three decades, and attempts to bring together state-of-the-art findings related to the role of neurosteroids in memory dysfunction, as seen in patients with schizophrenia, depression, and anxiety disorders.
The Role of Neurosteroids in Memory Deficits Associated With Stress and Anxiety Disorders
Three large scale major neural networks—the default mode network, central executive network, and salience network—contribute to cognitive processing within the human brain and function together to facilitate adaptive responses of the CNS
The default mode network plays a role in episodic memory function and self-related cognitive activities including autobiographical memories. Key functional nodes within the default mode network, which includes the hippocampus, amygdala, and medial prefrontal cortex, have been implicated in AD and epilepsy
The frontal parietal connections of the central executive network control attention, working memory, and executive function.
Responses to emotional changes and reward stimuli are dependent on intact function of the salience network, within which the anterior insula, anterior cingulate cortex and amygdala, ventral tegmental area, and thalamus function together to segregate the most relevant and rewarding among internal and extra-personal stimuli in order to guide behavior. Stronger connectivity within the salience network has been associated with increased anxiety
Neurosteroids play a role in anxiety and in the learning and memory deficits associated with certain anxiety disorders. Treatment of subjects under acute psychosocial stress with DHEA (50 mg/day) both improves attention but also impairs declarative memory function (78), suggesting that the benefits in one cognitive domain may be offset by deficits in another at this dose.
Neurosteroid modulation of GABAergic neurotransmission in the central amygdala has been implicated in anxiety (131) and the effects of ALLO on anxiety appear to be mediated in part via modulation of activity within the amygdala, which in turn influences neural activity in brain regions involved in learning and memory function
Selective serotonin reuptake inhibitors (SSRIs) increase brain levels of ALLO in humans and animals, suggesting that the anxiolytic effects of SSRIs may be related in part to their effect on CNS levels of this endogenous GABAergic modulator
When compared with normal subjects and patients with major depression, elderly patients with generalized anxiety disorder (GAD) show more deficits on tests of short-term memory function (305). The severity of GAD has been found to positively correlate with cortisol levels in saliva of older adults (73). Elevated salivary cortisol in older adults is associated with impaired performance on tests of memory function (306). Treatment of older adults presenting with GAD and elevated baseline cortisol with SSRIs is associated with a reduction in salivary cortisol that correlates with reductions in anxiety
Cortisol seems to enhance treatment outcomes in a small group (males and females) treated with exposure-based group therapy (310). In addition, high endogenous estradiol vs. low estradiol correlates with better treatment outcomes in exposure therapy (311) in female patients with spider phobias
Investigations of neural network activity using intracranial electroencephalography in human subjects indicate that β-frequency coherence (13–30 Hz) between the amygdala and hippocampus encodes variations in mood
DHEA and DHEAS appear to counteract the negative effects of increased cortisol on working memory function in women and men
A dose-dependent inverted U-shaped response to DHEAS is observed on tests of learning and memory function in male mice (30). By contrast, DHEA is effective in a wider range of doses, suggesting it would be a better choice as a therapeutic
The response to stress appears to be influenced in part by circulating steroid hormones. Stress increases associative learning and dendritic spine density in the hippocampus of male rats, but impairs associative learning and reduces spine density in females
The potential effects of neurosteroids on development of anxiety disorders can be observed during puberty, which is not only associated with increase in levels of reproductive hormones but also with the onset of many psychiatric disorders, including GAD, social anxiety, and panic attacks (320–326).
Of particular interest in this setting are the neurosteroids ALLO (in human and rat) and pregnanolone (in human only), metabolites of the reproductive hormone progesterone that are also produced in the brain in response to stress
Animal studies suggest that developmental exposure to ALLO influences subsequent responsivity to anxiolytics in adulthood
Acute stress is associated with an increase in plasma ALLO levels that correlates with an increase in expression of the TSPO, also known as the peripheral benzodiazepine receptor. Because the TSPO plays a role in steroidogenesis, it has been considered as a therapeutic target for treatment of anxiety disorders
It is interesting to note, that ALLO levels have been found to be decreased relative to controls in the CSF of women with chronic stress disorders, such as PTSD
These findings suggest that both acute stress and chronic stress give rise to unique effects on ALLO levels in men and women. Although studies in post-menopausal women did not reveal any benefit on tests of short-term memory function, it has nevertheless been suggested that replenishing this neurosteroid may have beneficial effects on memory function in certain populations with age-related memory deficits
Because PREG is a precursor for all steroid hormones, it seems plausible that promotion of cortisol synthesis during stress may attenuate synthesis of other steroid hormones, but this suggestion has not been substantiated.
These findings suggest that changes in endogenous brain levels of neurosteroids associated with age, sex, stress, and administration of SSRIs may play a key role in the onset and clinical response to pharmacologic interventions in certain anxiety disorders
The Role of Neurosteroids in Memory Deficits Associated With Depression
Changes in neurosteroid levels have been implicated in onset of depression and in the actions of medications used to treat depression. Animal studies using a synthetic analog of ALLO suggest that fluctuations in neurosteroids levels may also influence motivation to learn via modulation of dopaminergic pathways
The effects of ALLO on mood in women appear to follow an inverted U-shaped curve
SSRI treatment has been associated with increased brain levels of ALLO, suggesting that the memory enhancing effects of SSRIs in this patient population may be related in part to the actions of this neurosteroid
Preclinical animal studies suggest that modulation of GABAergic neurotransmission by DHEA may also have therapeutic potential in the treatment of memory deficits associated with depression
It has been suggested that PREG and its metabolites may be efficacious in the treatment of depressive disorders. Treatment of depression poses several challenges and this is especially true in the treatment of depression in bipolar disorder (BPD)
Synthetic Neurosteroids as Potential Cognitive Enhancers
The findings reviewed herein suggest that the memory deficits seen in patients with schizophrenia, depression and anxiety disorders are influenced by changes in endogenous neurosteroid levels.
synthetic analogs of neurosteroids, which are more resistant to metabolism and better able to cross the BBB, are under investigation for use as anxiolytics, antidepressants, cognitive enhancers, anesthetics, and anticonvulsants
The effects of neurosteroids in memory function in neuropsychiatric and neurologic disorders reflect their modulatory interactions exerted via selective binding at the amino and transmembrane domains of specific subunits comprising GABA and glutamate receptors, among others.
Age- and disease state-dependent changes in endogenous levels of neurosteroids appear to play a role in the emergence of the unique functional imbalances implicated in specific neuropsychiatric disorders and the associated memory deficits, which are mediated in part by changes in neural network activity within specific brain regions implicated in the encoding, consolidation, and retrieval of memories
It may be helpful to think of these findings in terms of a pharmacological connectome that reflects the interactions of neurosteroids with various neural networks involved with the encoding and recall of memories. We believe that a neural circuitry framework will help to guide future investigations into the potential role of neurosteroids and their synthetic analogs as neurotherapeutics for memory dysfunction
Pharmacologic connectivity pathways implicated in neurosteroidal modulation of memory function.
Neural networks that project to and/or share reciprocal connections with the hippocampus are modulated by neurosteroids as well as neurotransmitters. As a result, learning and memory deficits are associated with many of neurologic and neuropsychiatric disorders in which neurosteroids are implicated.
Neuroactive steroids, such as ALLO that enhance inhibitory neurotransmission can provide symptomatic relief from anxiety by reducing intra-network connectivity in the salience network and the amygdala
The effects of neurosteroids in memory function in neuropsychiatric and neurologic disorders reflect their modulatory interactions exerted via selective binding at the amino and transmembrane domains of specific subunits comprising GABA and glutamate receptors, among others. Age- and disease state-dependent changes in endogenous levels of neurosteroids appear to play a role in the emergence of the unique functional imbalances implicated in specific neuropsychiatric disorders and the associated memory deficits, which are mediated in part by changes in neural network activity within specific brain regions implicated in the encoding, consolidation, and retrieval of memories. It may be helpful to think of these findings in terms of a pharmacological connectome that reflects the interactions of neurosteroids with various neural networks involved with the encoding and recall of memories.
GADgeneralized anxiety disorder
HPA axishypothalamic-pituitary-adrenal axis